Rheumatoid Nodule Simulating a Parotid Tumor

Abstract

Rheumatoid nodules are an extra-articular manifestation of rheumatoid arthritis that are rarely found in the maxillofacial region. A 59-year-old woman with rheumatoid arthritis treated with methotrexate, leflunomide, and tocilizumab, presented with an enlarging mass in the left parotid region. Magnetic resonance imaging (MRI) displayed a lesion compatible with a neoplasm. However, an incisional biopsy showed features consistent with a rheumatoid nodule. The patient was managed conservatively, including cessation of methotrexate and initiation of treatment with hydroxychloroquine. At 15-month follow-up, the lesion had a significant reduction in size. To our knowledge, this is the first case report of a rheumatoid nodule in the parotid region. Although it is a rare manifestation, clinicians should consider this a possible differential diagnosis of parotid masses in patients with a history of rheumatoid arthritis or connective tissue disease.

Introduction

Rheumatoid nodules are the most common extra-articular manifestation of rheumatoid arthritis (RA) and are present in about 25% of patients with RA [1]. Rheumatoid nodules are often associated with high titers of rheumatoid factor (RF) or anti-citrullinated peptide antibodies (ACPA), and a more aggressive and erosive course of the disease [2]. Controversial studies have found associations between an increased risk of nodulous and specific genetic variants, cigarette smoking, and male gender [3]. Typically, rheumatoid nodules are subcutaneous and appear on the extensor surface of the proximal ulna and over pressure points such as the sacrum, Achilles tendon, occipital area and hand tendons [4]. They are rarely found in the maxillofacial region [5]. This report describes a case of a rheumatoid nodule located in the parotid region which initially mimicked a parotid tumor.

Case Report

A 59-year-old caucasian woman was referred for a maxillofacial surgery consultation due to a painless mass in the left parotid region with continuous growth over a 2 year period. (Fig. 1, left) The patient had a 20-year history of RF and ACPA-negative, as well as erosive RA associated with rheumatoid nodules. At that time, the RA was being managed with daily low dose prednisolone, subcutaneous methotrexate (MTX) (20 mg, per week, for 8 years), leflunomide (10 mg, per day, for 8 years), and monthly intravenous tocilizumab (8 mg/kg perfusion for 5 years) whereby stable low disease activity had been achieved (C-reactive protein disease activity score on 28 joints and CRP-DAS28 was 2.75). She was also an active smoker with a 30 pack-year history. The patient had no history of trauma and no additional head and neck symptoms. Examination revealed a 5 × 5 cm non-tender, firm to hard, fixed mass in the left parotid region, with normal overlying skin. There were an absence of neurological deficits and an absence of lesions or abnormalities in the oral cavity. Additionally, there were no clinically palpable lymph nodes in the neck.

Fig. 1.

Clinical image, anteroposterior view at first clinical evaluation (left) and posteriorly at 15-month follow-up evaluation (right)

A magnetic resonance imaging (MRI) scan was performed, which showed a 53 × 43 × 20 mm heterogeneous mass centered in the left masseter, compatible with a neoplasm, with probable invasion of the parotid gland. The mass appeared to extend beyond the temporal fossa, but with no clear signs of bone invasion. Additionally, the MRI confirmed that there were no cervical lymphadenopathies (Fig. 2).

Fig. 2.

Axial (left) and coronal (right) T2-weighted sequence MRI scan at the level of the mass with maximal maximal anteroposterior and transverse dimensions (left), as well as maximal craniocaudal dimensions (right) shown

An initial fine-needle aspiration (FNA) biopsy was performed but had provided a non-diagnostic tissue sample. Subsequently, the patient underwent a core needle biopsy, which confirmed the presence of adipose and fibrous tissue, as well as striated muscle tissue, that was extensively occupied by necrobiotic granulomas and surrounded by fibrosis. Moderate lymphoblastic inflammatory infiltrate of varying densities were also seen, characterised by multinucleate giant cells, some of which of the rare “Touton” type. The histologic findings were consistent with a rheumatoid nodule (Fig. 3).

Fig. 3.

Histopathological photomicrographs. Palisading histiocytes surrounding a central area of necrobiosis can be seen (HE 100 ×) (left). Detailed view of granulomatous reaction. Note the “Touton” type giant cells (HE 200 ×) (right)

The lesion was managed conservatively since the patient was otherwise asymptomatic. She was referred to her rheumatologist, which discontinued MTX and associated hydroxychloroquine; RA therapy with leflunomide and tocilizumbab was maintained. At the last follow-up, about 15 months after core needle biopsy, the nodule showed a significant reduction in size. (Fig. 1, right) In the patient’s opinion, there was a significantly larger reduction in size after initiating thiocolchicoside therapy, 4 months prior to the last evaluation.

Discussion

We present a case of a patient with a firm, non-tender mass in the parotid region, confirmed as a rheumatoid nodule by the pathology report. Rheumatoid nodules present clinically as solitary or multiple, non-tender, firm masses, with sizes varying from 2 mm to more than 5 cm [6]. As mentioned previously, they typically appear over pressure points, but can occasionally be seen in internal organs, such as the skin, lungs, heart, gastrointestinal tract, and cardiovascular and neurological systems [7]. Rheumatoid nodules in the maxillofacial region are extremely rare; nevertheless, there are reports in the literature of rheumatoid nodules in the buccal mucosa, lower lip, external ear, upper eyelid, nasal septum and nasal bridge, as well as the scalp, temporal bone and adjacent to the hyoid bone [5, 8–20] (Table 1). To the best of our knowledge, to date, there is no published case in English literature of rheumatoid nodule involvement of the masseter muscle and parotid gland. Similar to our case, however, many of the reports of rheumatoid nodules in the maxillofacial region had initial differential diagnosis that did not include rheumatoid nodules.

Table 1.

Cases of rheumatoid nodules in the maxillofacial region

Author	Author (years)/gender	Location	Presentation	Single/multiple nodules	Size (mm)	Duration of RA (years)	RA treatment	Initial Differential Diagnosis	Management	Follow-up
Skov [5]	79/F	Buccal mucosa	Painless	Single	7 × 6 × 5	21	No treatment	NI	Excision	No recurrence after 7 months
Tay et al. [8]	79/F	Buccal mucosa	Growing, painless	Single	13 × 16	NI	MTX and hydroxychloroquine	Fibroma, minor salivary gland tumor	Conservative treatment, discontinuation of MTX	NI
Ogi et al. [9]	60/M	Buccal mucosa	Erythematous, swelling of lymph nodes, tenderness in the submandibular region	Single	36 × 15	> 4	MTX	Malignant tumour	Conservative treatment, discontinuation of MTX	Spontaneously resolved in a 3 month period. No evidence of recurrence after 6 years
Kato et al. [10]	48/F	Lower lip	Slow-growing, painless	Single	8 × 8	12	NI	Fibroma, salivary gland lesion	Excision	No recurrence after 3 months
Healey et al. [11]	50/M	Nasal bridge and auricular antihelix	Painless, central ulceration	Multiple	5–6	20	NI	Basal-cell carcinoma	Conservative treatment	Spontaneously resolved in a 2 week period
	63/F	Nasal bridge and external ear	Painless, erythematous with central ulceration	Multiple	NI	15	Gold Therapy		Conservative treatment	Spontaneously resolved
	53/F	Nasal bridge and external ear	Painless, erythematous with central ulceration, suppurative	Multiple	3	25	NI		NI	NI
	62/F	Nasal bridge	Erythematous with central ulceration	Single	7	4	NI		Excision	No evidence of recurrence
	51/F	Nasal bridge	Painless, erythematous with central ulceration	Single	5	28	NI		Conservative treatment	Spontaneously resolved in a 3 month period
	56/M	Nasal bridge	Painless, erythematous	Multiple	5	NI	NI		NI	NI
	44/F	Auricular antihelix	Painless, crusted	Single	8	10	NI		NI	Spontaneously resolved
Horn et al. [12]	62/F	Auricular antihelix	Bilateral, painless, central ulceration	Multiple	3–5	3	NI	Extra-articular rheumatoid nodules, malignant tumour	Excision	No complications after 5 days
Carter et al. [13]	72/F	Upper eyelid	Purulent	Multiple	NI	15	Chlorambucil, gold salts, cyclophosphamide, and prednisone	Chalazion	Excision of one nodule for histologic diagnosis	One nodule persists at the 9- month follow-up
Bittenbender et al. [14]	73/M	Nasal bridge	Slow-growing, tender	Multiple	NI	NI	NI	NI	NI	NI
Belloso et al. [15]	82/F	Nasal septum	Painless, Mild nasal obstruction	Multiple	6	20	Gold therapy	NI	Excision	NI
Raven et al. [16]	62/F	Scalp (most marked on the forehead, but were scattered throughout the scalp)	Some adhered to skin and some adhered to epicranial aponeurosis	Multiple	1–3	NI	NI	NI	NI	The patient died of cardiac condition 16 days after initial observation
Kim et al. [17]	58/F	Scalp	Painless, Erythematous, Hard	Multiple	NI	25	NI	NI	Topical steroid	Regression in size after 1 month, with appearance of two new lesions
Hoffman et al. [18]	69/F	Temporal bone and middle ear	Otalgia, Otorrhea, difficulty moving the left side of her face, perforation of tympanic membrane with active suppuration, partial hemifacial paralysis of all divisions of the facial nerve	Multiple	NI	40	Various antiinflammatory drugs, Antimetabolites, Heavy metals and twenty years of continuous steroid use	NI	Surgical bony sequestration of temporal bone	Facial palsy resolved completely. The patient died of unrelated causes 30 months after her surgery
Gomez-Rivera et al. [19]	74/F	Adjacent to hyoid bone	Tenderness of the right base of tongue, with no palpable masses	Single	14	NI	MTX	Malignancy to the hyoid bone	Excision	No significant sequelae after 6 months. Maintained treatment with MTX
Bayram et al. [20]	49/F	Adjacent to Hyoid Bone (posterior left para-median of hyoid bone)	Dysphagia, sore throat and hoarseness	Single	13 × 9.33	25	Hydroxychloroquine, Sulfasalazine, Leflunomide	Neoplasm with a cystic component and metastatic carcinomas (signet ring or renal cell carcinoma)	NI	NI

F female, M male, MTX methotrexate, NI not informed, RA rheumatoid arthritis

MTX is a common and effective for the treatment of RA. However, its use has been associated with an increase in the formation of rheumatoid nodules and subcutaneous nodules may develop at a mean of three years after the start of MTX treatment [21]. The 2756GG genotype of the methionine synthase reductase gene, HLA-DRB1*0401, and RF positivity are predisposing factors for MTX-induced accelerated nodulosis [22–24]. There have also been occasional reports of accelerated drug-induced nodulosis associated with leflunomide, azathioprine, tocilizumab and anti-TNF agents, particularly etanercept [2, 24–26]. Moreover, MTX treatment may cause Epstein–Barr virus reactivation, which triggers the development of rheumatoid nodules [27]. In our patient, nodulous at the fingers and elbows were observed prior to the use of MTX in association with leflunomide and showed minor increases in size after initiating these therapies, but did not increase with the further addition of tocilizumab. Moreover, the accelerated development of a rheumatoid nodule in the parotid region during a period of low disease activity is consistent with the literature. One of the unusual and surprising features of our case is the seronegativity of the patient’s rheumatoid disease; indeed, the only noteworthy risk factor for nodulosis, in addition to the non-recent therapy with MTX and leflunomide, was a history of smoking.

The differential diagnosis for masses in the parotid region is extensive and includes inflammatory, neoplastic, autoimmune, traumatic and infectious lesions [28]. In our case, the unilateral, non-tender firm fixed mass in the parotid region was consistent with a benign or malignant neoplasm of the parotid gland, confirmed by MRI exam as a mass centered in the left masseter, compatible with a neoplasm, with probable invasion of the parotid. However, in this case, biopsy was essential in achieving the correct diagnosis, preventing unnecessary radical surgery.

Histologically, rheumatoid nodules generally appear as a granulomatous tissue reaction pattern with areas of necrobiosis and a surrounding palisade of histiocytes, with occasional lymphocytes, neutrophils, mast cells, and foreign body giant cells. Lymphocytes and plasma cells are present in a peripherally pattern that surrounds the palisading layer.

The management of rheumatoid nodules is conservative, as they are typically asymptomatic. Nodes should not be drained, injected or excised due to the high risk of infection and associated increase in recurrence rate [29]. Discontinuing MTX therapy can be considered in the management of these patients [30]. Alternatively, various drugs have been used in order to prevent nodulosis and/or control accelerated nodulosis, namely hydroxychloroquine, colchicine, D-penicillamine, sulfasalazine, tocilizumab and rituximab [31–36]. Additionally, there is a report of tomographic regression of pulmonary rheumatoid nodules under baricitinib, an inhibitor of janus kinase subtypes 1 and 2 [37]. No definitive recommendations can be made regarding the choice of the most appropriate biologic therapies for the treatment of RA patients with accelerated nodulosis, as the literature is scarce. Nevertheless, from what has been published, tocilizumab and rituximab are favored over anti-TNF agents. In our case, RA therapy was modified after diagnosis, specifically MTX was discontinued and hydroxychloroquine was initiated. Indeed, we observed a synergistic effect of both the aforementioned therapeutic measures. At the 15 month follow-up consultation, we observed that the lesion was significantly reduced in size. Interestingly, the patient reports an increased reduction after initiating treatment with thiocolchicoside. Currently, however, there are no reports in the literature to support a relation between this muscle relaxant and rheumatoid nodules. This may only be a case of patient perception, probably due to a reduction to some degree of the reactive contracture of the homolateral masseter muscle; however, more studies are needed to confirm this association.

Conclusion

Rheumatoid nodules are well-known lesions, which may be misdiagnosed as other lessons or tumours when presented in an uncommon location. Based on the literature review, this is the first case report of a rheumatoid nodule identified in the parotid region. Clinicians should consider rheumatoid nodules in the differential diagnosis of parotid masses in patients with a history of rheumatoid arthritis and/or connective tissue disease in order to prevent unnecessary radical surgery.