Androgen deprivation therapy in metastatic salivary duct carcinoma of submandibular gland – A case report

INTRODUCTION

Salivary duct carcinoma (SDC) was first described by Kleinsasser et al.^[1] in 1968, as an uncommon salivary gland tumor with a histological resemblance to ductal carcinoma of the breast. They reported the incidence of SDC as 1–3% among all salivary gland tumors. It usually affected elderly males and was found less often in young adults.^[2] This tumor was found to exhibit aggressive clinical behavior with a tendency for early cervical lymphadenopathy and distant metastases to the lungs and bones Thus, the prognosis of SDC was considered highly unfavorable. Aggressive clinical management, including radical surgery and postoperative radiation therapy in the early stage of the tumor, appeared to be the only treatment for long-term survival. The article by Moriki et al.^[3] clearly mentioned that the diagnosis of SDC is difficult and immunostaining for androgen receptor (AR) on cytological smears is useful for the diagnosis of these patients. A review of the literature indicated that immunohistochemically SDC expressed AR in the majority of the patients.^[4] The present case study reviews the clinical data of a patient with SDC in the right submandibular gland and discusses the role of androgen deprivation therapy (ADT) in such patients.

CASE REPORT

Patient consent was taken for journal submission as a case report. A 68-year-old lady presented to our outpatient clinic in January 2019 with a painless swelling of the right submandibular gland that had been apparent for a 2-month duration. It was painless initially but the patient experienced pain as it advanced to the present state. There was no history of fever or other constitutional symptoms. The patient also had no history of diabetes, hypertension, cardiac diseases, or tuberculosis. Physical examination revealed a firm lump of size 4*3 cm with restricted mobility in the right submandibular region which was not fixed to the overlying skin. There were multiple significant right level I, II, III, and level IV lymph nodes, and the largest one measured 2*1 cm. Further clinical examination did not reveal any abnormality in other head-and-neck sites including the oral cavity. Other systems including the central nervous system, cardiovascular system, respiratory, and gastrointestinal systems were normal.

DISCUSSION

SDCs are aggressive neoplasms generally affecting elderly males. Majority of the patients present rapidly enlarging firm masses with the propensity of cervical lymph node spread (40–80%).^[5] In the present case study, the patient was an elderly female with right cervical lymphadenopathy.

Due to the rarity of this neoplasm, the diagnosis of SDC is a clinical challenge both to the clinician and to the pathologist. The close differentials were metastatic lymph node and salivary gland carcinoma arising from the submandibular gland. Although SDC morphologically resembles ductal breast carcinoma the lack of expression of ER/PR may be helpful in the diagnosis.^[6] In SDC, 16–83% show HER2 expression. AR and HER2 expression is not specific for SDC; however, evaluation of AR or HER2 status is recommended to help guide therapeutic strategies. Trastuzumab-based HER2 targeted therapy can be tried in SDC s but this patient lacks its expression. Revised SDC classification based on biomarker immunoprofiling by Takase et al.^[7] is useful for predicting the patient’s survival or for selecting appropriate therapy. Based on biomarkers Takase et al. classified SDCs into four groups: 1. Apocrine A (AR+/HER2−/Ki-67-low), 2. Apocrine B (AR+/HER2−/Ki-67-high), 3. Apocrine HER2’ (AR+/HER2+), and 4. Double negative (AR−/HER2−).

SDC is a rare and aggressive salivary gland malignancy for which treatment is surgical resection and neck dissection, with adjuvant radiation therapy reserved for the more advanced forms. However, the 5-year recurrence-free survival rate remains at ~30%.^[8] Immunohistochemical studies are necessary for a definite diagnosis. ADT evolved from the treatment of prostatic cancers and is definitely an option for those patients with metastatic disease. The present case showed improved outcomes with Abiraterone and enzalutamide-based treatment.

Abiraterone acetate was identified to be a potent and selective irreversible inhibitor of CYP17. The CYP17 enzyme is a cytochrome P450 (CYP) enzyme. Located in the endoplasmic reticulum of the testis, ovaries, adrenals, and placenta, CYP17 drives the synthesis of glucocorticoids and sex hormones.^[9] Abiraterone acetate is proven to be effective in suppressing testosterone and showed survival benefits in prostate cancers. Enzalutamide (formerly known as MDV3100) is a rationally designed and targeted AR inhibitor that competitively binds to the ligand-binding domain of the AR and inhibits AR translocation to the cell nucleus, recruitment of AR cofactors, and AR binding to deoxyribonucleic acid. Enzalutamide significantly prolongs the survival of men with metastatic castration-resistant prostate cancer after chemotherapy.^[10]

Furthermore, additional studies focusing on the etiology, mechanism of SDC, and targeting of ARs are required.

CONCLUSION

Two important biomarkers identified in SDCs are ARs and HER2 receptors. This case study represents the successful treatment of a metastatic SDC of the right submandibular gland with multimodality treatment including AR-targeted agents. The patient already achieved a disease-free survival of 30 months and the treatment is still going on. Further studies are required to target ARs and more agents are to be tried in this clinical setting.