It is considered that the initial report of orofacial granulomatosis was made by Melkersson in a patient with facial swelling and paralysis [6]. In 1945, Miescher published the first case of “granulomatous cheilitis” on the upper lip [14]. This granulomatous cheilitis can be accompanied by other oral and facial signs such as ulcerations, gingival overgrowth, lingual lesions, etc., constituting what is known as “orofacial granulomatosis” [4]. This term groups different disorders that characteristically affect the upper lip, and whose clinicopathological differentiation is difficult in many cases [15, 16].

The initial differential diagnosis of granulomatous cheilitis has to be made between infectious and non-infectious processes, but infectious granulomatous cheilitis of the upper lip are rare [17, 18].

Different systemic entities can cause upper lip granulomas and Crohn’s disease is the most emblematic [3]. Crohn’s disease is a chronic inflammatory digestive disorder, whose first clinical manifestation can be oral in up to 30% of cases [19]. The oral presentation is highly variable; however, a cobblestone appearance of the mucosa, lip swelling, linear ulcerations and mucogingivitis are the most common oral findings [20]. In our case, the patient was already aware of her systemic condition. When the oral cavity is the first affected site, final diagnosis is obtained after performing a complete clinical history, intestinal endoscopy and blood tests [19]. Microscopically, the lesions show non-caseating granulomas and chronic inflammation which can extend to involve the salivary gland parenchyma, similar to our case [21]. Interestingly, only the granulomas seen in the case of Chron’s reached the salivary gland parenchyma, which may be helpful for the differential diagnosis of granulomas associated with Chron’s or sarcoidosis with the other subtypes of NIGDUL [3].

The list of esthetic materials associated with granulomatous reaction is extensive: silicone, collagen, hyaluronic acid, calcium hydroxyapatite, etc. [22]. Since patients often do not report the cosmetic procedures they receive, it is very important to perform a good medical history to reach the final diagnosis [22, 23]. Liquid silicone is a hydrophobic polymeric of dimethyl siloxane compounds, whose granulomatous reaction characteristically shows a vacuolar macrophagic appearance [24, 25]. This bubbling or vesicular pattern of the cytoplasm can mimic other pathologies, like liposarcoma and mucoepidermoid carcinoma [26]. Calcium hydroxyapatite (CaHA) is another esthetic filler material consisting of spherical particles embedded in an aqueous gel of carboxymethylcellulose and glycerine [27]. CaHA is an inorganic element of the bone and teeth; yet, it is unknown why more than 10% of patients develop a foreign body reaction [28]. Microscopically, the particles appear surrounded by a histiocytic granulomatous reaction with giant cells [29]. Unlike NIGDUL associated with Crohn’s disease, the granulomatous reaction of this subtype was deeper and did not show chronic lymphocytic inflammation.

The third subtype of our study referred to patients who, in addition to the lip swelling, also presented areas of erythema and erosion on the lip mucosa, with a symmetric desquamative gingivitis lichenoid-like in the upper anterior gingiva. Robinson et al. (2006) [10] were the first to describe this disorder as “lichenoid granulomatous stomatitis”. Microscopically, these lesions showed lip granulomatosis, chronic mucositis, areas of basal degeneration and Civatte bodies [10, 11]. In our opinion, “lichenoid granulomatous stomatitis” is not a good name for this disorder, since oral lichenoid disease requires the presence of whitish papular [reticular] lesions in other areas of the oral mucosa, which were not seen in our patients [30]. Furthermore, oral lichenoid disease does not have pathognomonic histopathological features and desquamative gingivitis may appear in other mucocutaneous diseases [31].

Macrophage activation is a complex process involving the complement system (C3b, C5a) and multiple proinflammatory cytokines (TNF, IL-1, IL-6, IL-17 and IFN gamma), via T cell activity [32]. Accordingly, chronic lymphoplasmacytic inflammation maintains the stimulus for the granulomatous response [33]. This granulomatous inflammation encompasses a wide spectrum of histopathological findings, from well-constituted granulomas to clusters of histiocytes admixed with other inflammatory cells [5]. The variation of this granulomatous response depends on different factors, including the location [5], which could explain the different histological aspects of the biopsies of NIGDUL associated with gingivitis lichenoid-like. We believe that, in these cases, there could be contact feedback between the mucosa of the swollen lip and the gingiva. Therefore, it is mandatory to perform a good clinical history to identify local, dental or not, irritative factors.

When faced with a swollen and granulomatous upper lip in which all the previous possible diagnoses have been ruled out, our only option is to call these lip lesions NIGDUL NOS or idiopathic [9]. NIGDUL NOS would be included under the idiopathic orofacial granulomatosis spectrum, which includes cheilitis granulomatosa of Miescher and Melkersson–Rosenthal syndrome (MRS). NIGDUL NOS could be considered as a monosymptomatic form of MRS; thus, it is very important to differentiate both pathologies, since patients with MRS also develop neurologic manifestations, like facial nerve palsy [34]. Several theories have been postulated to explain the development of NIGDUL NOS, such as exposure to food, beverages, toxins, dental materials, etc. [4]. In this condition, there is a patchy, scattered chronic inflammatory infiltrate and the granulomas are most commonly seen in proximity to the vascular structures. We suspect that one of our patients [female, 56 years] could be an early manifestation case of the third subtype [associated with lichenoid-like gingivitis], in which gingival lesions have not yet appeared; thus, precluding the diagnosis of NIGDUL associated with gingivitis lichenoid-like.

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