Neoadjuvant Chemotherapy as a Viable Treatment Option for Locally Advanced Adenoid Cystic Carcinoma of Salivary Gland: a Case Report

Adenoid cystic carcinoma (ACC) is a rare infiltrative tumor predominantly affecting minor salivary gland along with submandibular and parotid glands. Its biological behavior has not been clearly understood, and only few researches have been performed regarding treatment options. Patient usually presents with swelling of salivary gland region with complaints of paresthesia, numbness, and pain or muscle weakness due to nerve involvement. Diagnosis is confirmed on histopathology, and surgical excision is the treatment of choice in resectable cases. The role of neoadjuvant chemotherapy or radiotherapy remains debatable in advanced presentation. Present case depicts the role of chemotherapy and radical surgery in its management. Here, we present a case of recurrent locally advanced ACC that was down staged and underwent R0 resection after neoadjuvant chemotherapy (NACT). After two and half years of follow-up, the patient is alive and disease-free. Adenoid cystic carcinoma (ACC) is a rare and aggressive variant of salivary gland neoplasm. Perineural invasion and resistance to present chemotherapeutic drugs makes treatment more challenging. Role of chemotherapy remains controversial and in upfront technically unresectable cases neoadjuvant chemotherapy (NACT) can be used as an option to achieve R0 resection.


Introduction
The salivary gland tumors are rare neoplasm of head and neck region, and only 20% are found to be malignant [1]. Adenoid cystic carcinoma (ACC) accounts for 10-20% of all malignant tumors of salivary glands [1,2]. Despite having slow growth kinetics ACC represents important therapeutic challenge because of its tendency of perineural invasion, thus posing a challenge to surgical resection and subsequent high chances of recurrence [1,2]. For localized disease, surgery remains the cornerstone of treatment. In the absence of longterm data, most of the clinicians recommend post-operative radiotherapy to reduce the relapses. Primary treatment with radiation is considered when surgery is not feasible [2,3].
Role of chemotherapy is still investigational and mainly remains limited to advanced and metastatic disease with poor outcomes [4]. Neoadjuvant chemotherapy (NACT) has shown promising results in various studies in locally advanced cancers of oral cavity [5]. Considering the dearth of NACT as treatment modality, the present case reports a locally advanced ACC that was down staged by NACT and further underwent a R0 surgical resection.

Case Presentation
A 50-year-old gentleman presented with a three months history of recurrent swelling in left buccal mucosa and left neck region. He was operated twice before presenting to our center. First excision was one year back via trans-oral route, and he developed recurrence after three months of first surgery. He underwent repeat surgery six months back via cheek incision; however, detailed operative notes and histology reports were not available. On examination, a healed scar was present over left cheek in pre-parotid region; This article is part of the Topical Collection on Surgery intraoral examination showed only a small ulcer over left buccal mucosa near parotid duct opening. On bimanual palpation, a 3 × 3-cm submucosal mass was present in left buccal mucosa, densely adherent to overlying scar. Another 5 × 5-cm matted nodal mass was present in levels Ib, II, and III. Core needle biopsy from nodal mass was suggestive of adenoid cystic carcinoma Contrast CT scan showed left buccal mucosa mass with matted nodal mass in levels Ib, II, and III and no lung metastasis (Fig. 1). In view of rapidly recurring primary and matted lymph nodes, tumor was deemed technically unresectable, and decision for neoadjuvant chemotherapy was taken in multidisciplinary clinic. He received three cycles of paclitaxel (175 mg/m 2 ) and carboplatin (AUC-5) at three weekly intervals. After three cycles, patient had partial response (approximately 60% regression in primary tumor and 80% regression in nodal mass). Post chemotherapy MRI showed near complete reduction in size of the nodal mass (Fig. 1).
Patient underwent wide excision of primary tumor with superficial parotidectomy and modified type II neck dissection (levels I-V). The skin and soft tissue defect was reconstructed with bipedal pectoralis major myocutaneous flap (PMMC). Postoperative recovery was uneventful. Final histology showed adenoid cystic carcinoma of minor salivary gland with clear margins and 2 lymph nodes (both level IIb) showed metastatic tumor deposit out of 42 dissected nodes (Fig. 2). He received postoperative 60 Gy radiotherapy to the primary and neck region. After three years of follow-up, the patient is disease-free.

Discussion
Adenoid cystic carcinoma (ACC) accounts for 1% of all head and neck cancer; majority arise from minor salivary glands, and oral cavity is the most common sub site [1,2]. Surgery remains the cornerstone of treatment whenever feasible in localized disease, and radical radiation/chemoradiation is only considered an option when tumor is deemed unresectable [1][2][3]. Despite achieving margin negative resection, local recurrences and distant metastasis are quite common after surgery. Perineural invasion seen in 10-30% cases is peculiar feature of ACC and may be responsible for such high risk local recurrences [2,3]. Adjuvant radiotherapy is an option to reduce the postoperative recurrence in intermediate or high grade ACC or ACC resected with close or positive margin. Various retrospective studies have shown that radiotherapy seems to reduce local recurrences but the impact on survival is still not clear [6,7]. Incidence of lymph node metastasis varies from 14 to 20% in salivary gland neoplasm [8]. In ACC, chances of lymph node metastasis are low in compare to other salivary neoplasm; however, in the present case, extensive nodal disease was present making it not suitable for upfront surgery.
In view of slow growth kinetics, most of the ACC shows low response rate and do not benefit from chemotherapy.
Chemotherapy and targeted therapy in ACC are mainly limited to recurrent and metastatic disease with poor outcomes [4,6]. In older studies, single agent chemotherapy using 5 fluorouracil, cisplatin (CDDP), mitoxantrone, and epirubicin showed good response, whereas newer studies have shown benefit with paclitexal, gemcitabine, and vinorelbin. The most common studied regimen in combination chemotherapy cisplatin, doxorubicin, and cyclophosphamide (CAP) is very toxic and not standard of care. We choose combination of paclitexal and carboplatin because this combination has shown good efficacy in few recent studies with minimal toxicity [4,6]. Few retrospective studies have shown the benefit of neoadjuvant chemotherapy (NACT) in very advanced, technically unresectable oral cancer patients [5]. In view of rarity of disease, no good quality data exists regarding use of NACT in ACC or other salivary neoplasm [9,10]. Only few case reports have shown role of NACT in locally advanced salivary neoplasm [11,12].
In present case in view of advanced nodal disease, we used NACT as an option as it was technically unresectable upfront and got a good response to chemotherapy. He underwent radical surgery with successful R0 resection. So in selected locally advanced/upfront unresectable cases, NACT can be a practical therapeutic tool.