Bone Metastasis as Initial Presentation of an Aggressive Adenoid Cystic Carcinoma of Mandible: Case Report

1. Abstract Adenoid cystic carcinoma (ACC) is a slowly growing malignant neoplasm with possible widespread distant metastasis. The diagnosis requires thorough clinical, radiological and histopathologic examination. Here, we report a case of a 40-year-old male who presented back pain, paresthesia, dysphagia and swelling around the left mandibular region. He was referred to our rheumatology department to explore a multiple vertebral and iliac involvement revealed by initial imaging including computed tomography (CT) and magnetic resonance imaging (MRI). His physical examination showed a 3×2 cm hard fixed and mass in the left mandibular region and a right facial palsy.

2. Introduction Adenoid cystic carcinoma (ACC) is a malignant tumor that may affect either the major or minor salivary glands of the oral cavity [1]. It occurs most often in minor salivary glands and the submandibular gland, and less frequently in the sublingual and parotid glands. Other rare locations include lacrimal and ceruminous glands as well as other sites in the head and neck, including the nasal and paranasal sinuses, trachea and larynx [2]. Although it presents a widespread age distribution, peak incidence occurs predominantly among women, between the 5th and 6th decades of life [3]. ACC is a relentlessly growing tumor characterized by perineural invasion and multiple local recurrences. Regional lymph node metastases are rare. In sharp contrast, hematogenous metastasis is common, especially to lung, bone and liver [4]. This tumor remains, an extremely difficult disease to treat and that is why it was described by Conley and Dingman as “one of the most biologically destructive and unpredictable tumors of the head and neck” [5]. We report a case of adenoid cystic carcinoma of the submandibular gland revealed by bone metastasis in a 40-year-old man.

3. Case Presentation A 40-year-old male complained of back pain for about three months. The pain had gradually increased in intensity, with a loss of ambulatory capacity and general weakness. Initial imaging (including CT and MRI) showed multiple vertebral and iliac involvement and the patient was referred to our rheumatology department for exploration (Figure 1). Medical history revealed that he was suffering from pain, paresthesia, dysphagia and swelling around the left mandibular region and had visited a local dental clinic for the same complains, nine months ago. He also reported alcohol consumption and cigarette smoking. The physical examination revealed a 3×2 cm hard and fixed mass in the left mandibular region, but contrary to our expectations, a right facial palsy (Figure 2). The overlying skin was intact, and no ulceration was noted. Neither motor nor sensory deficit was observed but there was a mild limitation in the hip flexion and extension range of motion in the right hip joint. Initial laboratory investigations revealed white blood cells count of 13270/ml, hemoglobin level of 10,5 gr/dl and platelets count of 193300/ml. The erythrocyte sedimentation rate was high (65 mm) and the C-reactive protein level was high (41mg/ml). Serum calcium was increased at 4.66 mmol/L (2.2–2.6 mmol/L) and the creatinine at 320 µM/L. Serum parathormone was low (6ug/ml). Urgent treatment of this malignant hypercalcemia was started, combining intensive hydration, diuretics, corticosteroids and bisphosphonates. Our patient didn't respond initially to any of these treatments and a good control of this hypercalcemia was obtained after dialysis. Then, the patient was referred to the otorhinolaryngology department to explore the right facial palsy and to search for the primary neoplasm. On examination, it was confirmed a grade V right facial palsy (Facial grading of House and Brackman) with a smooth bulge involving the left side of soft palate. The tonsil was pushed medially. The swelling was firm, mobile and covered with intact mucosa. Cranio-facial CT and MRI showed a 6 * 4.5 * 4 cm left para pharyngeal tissue mass infiltrating the pre-stylian, infra temporal fossa, the pterygoid muscles and the temporal muscle with discreet deviation of the oropharyngeal pathway to the right. it invades the ramus and the horizontal branch of the left mandible with rupture of the vestibular and lingual cortex (figure 3). The tumor invades the base of the skull with endocranial extension. No cervical lymphadenopathy was noted. Endocranial extension was noted with the invasion of the tent of the cerebellum on the left side, a lateral infiltration of the cerebral trunk, the pre-pontic and pre-peduncular cisterns. A core biopsy of the bone lesion was carried out and histopathologic analysis showed an invasive tumor, made by solid nests and cribriform areas. A clump of basaloid epithelial cells containing a fluid similar to mucus in the lumen was found out. This cribriform pattern of the lesion gave the entire structure a typical “swiss cheese” appearance. Atypical tumor cells were detected and immunohistochemical study revealed that tumor cells are diffusely positive C-kit (CD117). Based on the above features, the diagnosis of ACC of possible salivary gland origin was given (Figure 4). Based on the overall clinical, radiographic, and histologic findings, a diagnosis of metastatic ACC was made. The tumor was deemed unresectable, therefore palliative treatment by chemotherapy and radiotherapy was indicated. Unfortunately, none of these treatments was given and the patient died one month later.

4. Discussion Adenoid cystic carcinoma is an uncommon tumor of salivary gland origin. The first term used to describe the histological finding was « cylindroma » by Billroth in 1859 and it was later renamed by Foote and Frazell in 1953 as « adenoid cystic carcinoma » [6]. Although ACC can occur in all age groups with a peak incidence age between the fourth and sixth decades, with no gender predilection [7]. It usually presents as slowly growing firm unilocular mass in the gland and the duration of the lesion, prior to initial presentation, may vary from less than 1week to several years [8]. Despite its slowly growing, this tumor is highly invasive with a high recurrence rate. Pain and swelling of the jaw are the most frequent clinical presentations [6,9,10]. Paresthesia, muscle weakness, tooth mobility and trismus are an uncommon finding. Although the most common initial presentation is unclear. The posterior body and the angle of the mandible were most commonly occurred [11]. The occurrence of bone metastasis usually corresponds to rapid tumor dissemination and death of the patient, such as illustrate our case, whereas lung metastases demonstrate a less aggressive clinical course [12]. Although the pathogenesis of ACC remains unclear and the tumor can be difficult to assess clinically, so a diagnostic criterion was proposed and established: radiographic evidence of osteolysis, presence of intact cortical plates, absence of a primary tumor within the major or minor salivary glands, and histological confirmation of the typical architectural and morphological features of ACC [13,14]. However, CT and MR imaging remains useful in surgical planning, especially to delineate the extent, local invasion, and perineural spread of the tumor. The lesions are generally poorly defined and have infiltrative margins [15]. Histologically, there are three variants of the ACC: cribriform, tubular and solid. The cribriform variant is the most classic, which is characterized by islands of basaloid epithelial cells that contain multiple cylindric, cyst-like spaces resembling swiss cheese [16]. The tubular pattern is characterized by glandular spaces of elongated tubules lined by epithelial cells and surrounded by single or multiple layers of basaloid cells. The solid pattern is composed of solid epithelial islands with central areas of necrosis; the cells are small, basophilic and hyperchromatic with a densely granulated nucleus [17]. A well-established analysis of histopathological findings is necessary to confirm the final diagnosis of ACC. Furthermore, many other settings could influence the prognosis of this tumor such as the perineural invasion and lymph node metastasis [18]. Immunohistochemical (IHC) study show positive expression of myoepithelial cells for S100, p40 and cytokeratins (CKs), while ductal cells express strongly CK 7 [16]. ACC shows usually strong and diffuse positivity for c-KIT (CD117) in tumor cells in the solid pattern, all cells surrounding cyst-like spaces in the cribriform pattern, and luminal cells in the tubular pattern [19]. The treatment of ACC is influenced by location of the tumor, stage at diagnosis and the histologic grade [20]. The treatment of choice is radical surgical resection, ensuring free margins, and postoperative radiotherapy [21]. Mendenhall et al, compared radiotherapy alone to radiotherapy combined with surgery and concluded that combination treatment is preferable [22]. Unfortunately, local recurrences occur despite combined treatment with surgery and radiotherapy. The 5 to 10-year recurrence rates range from 30% to 75% [23]. Several chemotherapy studies have been performed over the years. The results show consistently low response rates to cytotoxic chemotherapy for metastatic disease [24]. In patients with adverse prognostic factors, some studies showed that concurrent chemoradiotherapy, especially with platinum-based chemotherapy seems to be effective in improving locoregional control [25]. In a few cases, temporary partial disease response or stabilization may be achieved. The current consensus is that chemotherapy should be reserved for patients with symptomatic metastases or rapidly progressing disease who are not candidates for other treatment modalities [24]. Due to the ineffectiveness of cytotoxic chemotherapy in advanced ACC, several ongoing trials are testing agents that inhibit fibroblast growth factor receptor signaling or other signaling pathways. Novel treatments based on the recently sequenced tumor genome are under development [26,27].

5. Conclusion Due to the exceedingly rare occurrence of ACC and its extremely slow growth pattern, the diagnostic remains a challenge to every clinician. However, this tumor has usually fatal outcome especially when the diagnosis is made due to the appearance of metastasis. The present case illustrate that salivary gland tumors should be considered as origin of bone metastasis which is uncommon. Long-term follow-up is imposed to rule out regional and distant metastases in patients with intraosseous ACC.

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Ben Chekaya Narimane. Bone Metastasis as Initial Presentation of an Aggressive Adenoid Cystic Carcinoma of Mandible: Case Report. A Single Center Experience. Annals of Clinical and Medical Case Reports 2022