This site remains under construction. The information below is solely provided to demonstrate the functionalities and features of the RDOD.
Mammary Analog Secretory Carcinoma
Site editors: Shivani Sud MD and Courtney Vaugh, MPhil, MD PhD Candidate
Background
Mammary analogue secretory carcinoma (MASC) is a rare salivary gland tumor (SGT) first described by Skalova et al. in 2010 [1]. MASC typically arises in the head and neck region with highest frequency in the parotid gland and is named for histologic characteristics similar to breast secretory carcinoma including cystic, tubular or papillary structures containing eosinophilic vacuolated cytoplasm [1–3]. The associated hallmark mutation, a t(12;15)(p13;q25) balanced translocation, forms the ETV6-NTRK3 fusion gene encoding an oncogenic chimeric tyrosine kinase with downstream effect on Ras-MAPK and PI3K-AKT pathways [1,3–5]. No standard therapy exists and reports of treatment and outcomes are limited as many cases were identified during retrospective review of institutional SGT archives. Prior to knowledge of this translocation, these were previously histologically classified most commonly as acinic cell carcinomas, mucoepidermoid carcinoma, or adenoid cystic carcinomas. [1,6]. While MASC is regarded as a low-grade malignancy, high-grade transformation, metastasis and death from disease have been described [2,7].
Cases published to date
Approximately 200 cases of MASC have been published in the medical literature to date. These reports include a mix of clinical reports and pathology reports. We have created a running systematic review table by extracting pertinent clinical information from each of these reports to facilitate clinical and research aims. Tables are organized with the headers below. Diagnostics for MASC are customized to include the method by which the presence of the ETV6-NTRK3 fusion gene was assessed. Spreadsheet Tab 1 contains abstracted data for all case reports to date. Spreadsheet Tab 2 contains published review articles to date.
| masc_case_listing_and_review_papers.xlsx |
*For this disease site, tables remain under construction at this time.
Cases published by RDOD
A total of 1 case report on MASC has been submitted to the Journal of the RDOD.
Discussion
Malignant salivary gland tumors, encompassing widely heterogeneous tumor types, are rare with an estimated annual incidence rate of 0.9 cases per 100,000 individuals [8]. MASC is a recently defined neoplasm first added to the WHO Classification of Head and Neck Tumors in 2017 [9]. Our query of the United States sponsored Surveillance Epidemiology and End Results Program as of February 2018 showed only 42 cases of secretory carcinoma (ICD-0-3 8502/3) of the oral cavity and pharynx with minimal therapy related data [10]. The novelty and rarity of MASC preclude derivation of evidence-based treatment guidelines. Therapeutic approaches in case reports vary regarding extent of excision, performance of neck dissection and use of adjuvant chemotherapy or radiation therapy.
Histologically, MASCs are not highly infiltrative and like its closest histologic mimic, acinic cell carcinoma, is regarded as a low-grade carcinoma. However, aggressive clinical behavior including recurrence, metastases and death have been reported [7]. Diagnostically, MASC can be differentiated acinic cell carcinoma, based on positive staining for S-100 and mammaglobin, absence of fine zymogen granules on periodic acid Schiff (PAS) with diastase and canonically the presence of the ETV6-NTRK6 fusion gene. Although this fusion gene is also reported in breast secretory carcinoma, infantile fibrosarcoma and congenital mesoblastic nephroma, MASC is regarded as a distinct entity.
Therapeutic approaches in the literature are wide-ranging. Herein, we briefly review principles of adjuvant therapy including radiation and chemotherapy for salivary gland tumors as they may apply to tumors with locoregional metastases or concern for high-risk malignancy. Stages I and II include tumors without extraparenchymal extension that are <2cm and >2cm but <4cm, respectively, which are managed surgically. Stages III and IV include tumors >4cm and/or extraparenchymal extension, local invasion (skin, mandible, ear canal, facial nerve, bone), encasement of the carotid artery or lymphatic spread. Consideration for post-operative radiation therapy (PORT) with minimum dose of 60 Gy should be given to tumors with any of the following characteristics: advanced stage (III or IV), high-grade histology, incomplete resection or close margins (<5mm), suspicion for residual neck disease, extracapsular LN spread or recurrent disease [11,12].
In a retrospective analysis of 538 patients treated for salivary gland cancer by the Dutch Head and Neck Oncology Cooperative Group, risk factors for LN metastases included increasing T stage and histology [12]. In the same analysis, for pN1 neck node control was 83% after locoregional PORT compared to 57% without nodal irradiation. Based on study of dose-response relationships within the study population, the authors recommend a dose of 60Gy for local PORT, 46 Gy to nodes levels I-III for elective treatment of neck nodes, 60Gy to Level I-V nodes for known pN+ disease and when primary surgical invention is precluded, a dose of 66-70Gy to the primary [12]. There are no standard guidelines for use of systemic therapy in salivary gland tumors [13]. An exhaustive review of chemotherapy data in salivary gland tumors found platinum, 5-Fluorouracil and anthracyclines are likely the most effective agents but response rates to systemic chemotherapy and targeted therapies are generally low [13]. Several clinical trials of adjuvant chemoradiation are ongoing [14].
When considering a cancer as rare as salivary gland tumors and in particular, the new entity of MASC, data is limited to case reports and series. We strongly encourage publication of clinical data including disease presentation, treatment course and follow up for reported cases.
Histologically, MASCs are not highly infiltrative and like its closest histologic mimic, acinic cell carcinoma, is regarded as a low-grade carcinoma. However, aggressive clinical behavior including recurrence, metastases and death have been reported [7]. Diagnostically, MASC can be differentiated acinic cell carcinoma, based on positive staining for S-100 and mammaglobin, absence of fine zymogen granules on periodic acid Schiff (PAS) with diastase and canonically the presence of the ETV6-NTRK6 fusion gene. Although this fusion gene is also reported in breast secretory carcinoma, infantile fibrosarcoma and congenital mesoblastic nephroma, MASC is regarded as a distinct entity.
Therapeutic approaches in the literature are wide-ranging. Herein, we briefly review principles of adjuvant therapy including radiation and chemotherapy for salivary gland tumors as they may apply to tumors with locoregional metastases or concern for high-risk malignancy. Stages I and II include tumors without extraparenchymal extension that are <2cm and >2cm but <4cm, respectively, which are managed surgically. Stages III and IV include tumors >4cm and/or extraparenchymal extension, local invasion (skin, mandible, ear canal, facial nerve, bone), encasement of the carotid artery or lymphatic spread. Consideration for post-operative radiation therapy (PORT) with minimum dose of 60 Gy should be given to tumors with any of the following characteristics: advanced stage (III or IV), high-grade histology, incomplete resection or close margins (<5mm), suspicion for residual neck disease, extracapsular LN spread or recurrent disease [11,12].
In a retrospective analysis of 538 patients treated for salivary gland cancer by the Dutch Head and Neck Oncology Cooperative Group, risk factors for LN metastases included increasing T stage and histology [12]. In the same analysis, for pN1 neck node control was 83% after locoregional PORT compared to 57% without nodal irradiation. Based on study of dose-response relationships within the study population, the authors recommend a dose of 60Gy for local PORT, 46 Gy to nodes levels I-III for elective treatment of neck nodes, 60Gy to Level I-V nodes for known pN+ disease and when primary surgical invention is precluded, a dose of 66-70Gy to the primary [12]. There are no standard guidelines for use of systemic therapy in salivary gland tumors [13]. An exhaustive review of chemotherapy data in salivary gland tumors found platinum, 5-Fluorouracil and anthracyclines are likely the most effective agents but response rates to systemic chemotherapy and targeted therapies are generally low [13]. Several clinical trials of adjuvant chemoradiation are ongoing [14].
When considering a cancer as rare as salivary gland tumors and in particular, the new entity of MASC, data is limited to case reports and series. We strongly encourage publication of clinical data including disease presentation, treatment course and follow up for reported cases.
References
- Skálová A, Vanecek T, Sima R, Laco J, Weinreb I, Perez-Ordonez B, et al. Mammary Analogue Secretory Carcinoma of Salivary Glands, Containing the ETV6-NTRK3 Fusion Gene: A Hitherto Undescribed Salivary Gland Tumor Entity: Am J Surg Pathol 2010:1. doi:10.1097/PAS.0b013e3181d9efcc.
- Kratochvil FJ, Stewart JCB, Moore SR. Mammary analog secretory carcinoma of salivary glands: a report of 2 cases in the lips. Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:630–5. doi:10.1016/j.oooo.2012.07.480.
- Bishop JA. Unmasking MASC: Bringing to Light the Unique Morphologic, Immunohistochemical and Genetic Features of the Newly Recognized Mammary Analogue Secretory Carcinoma of Salivary Glands. Head Neck Pathol 2013;7:35–9. doi:10.1007/s12105-013-0429-0.
- Wai DH, Knezevich SR, Lucas T, Jansen B, Kay RJ, Sorensen PH. The ETV6-NTRK3 gene fusion encodes a chimeric protein tyrosine kinase that transforms NIH3T3 cells. Oncogene 2000;19:906–15. doi:10.1038/sj.onc.1203396.
- Lannon CL, Sorensen PHB. ETV6–NTRK3: a chimeric protein tyrosine kinase with transformation activity in multiple cell lineages. Semin Cancer Biol 2005;15:215–23. doi:10.1016/j.semcancer.2005.01.003.
- Bishop JA, Yonescu R, Batista D, Eisele DW, Westra WH. Most Nonparotid “Acinic Cell Carcinomas” Represent Mammary Analog Secretory Carcinomas: Am J Surg Pathol 2013;37:1053–7. doi:10.1097/PAS.0b013e3182841554.
- Sethi R, Kozin E, Remenschneider A, Meier J, VanderLaan P, Faquin W, et al. Mammary analogue secretory carcinoma: Update on a new diagnosis of salivary gland malignancy: New Diagnosis: MASC. The Laryngoscope 2014;124:188–95. doi:10.1002/lary.24254.
- Pinkston JA, Cole P. Incidence Rates of Salivary Gland Tumors: Results from a Population-Based Study. Otolaryngol-Head Neck Surg 1999;120:834–40. doi:10.1016/S0194-5998(99)70323-2.
- El-Naggar AK, Chan JKC, Grandis JR, Takata T, Slootweg PJ, editors. WHO classification of head and neck tumours. 4th edition. Lyon: International Agency for Research on Cancer; 2017.
- Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Incidence - SEER 9 Regs Research Data, Nov 2016 Sub (1973-2014) <Katrina/Rita Population Adjustment> - Linked To County Attributes - Total U.S., 1969-2015 Counties, National Cancer Institute, DCCPS, Surveillance Research Program, released April 2017, based on the November 2016 submission. n.d.
- Sood S, McGurk M, Vaz F. Management of Salivary Gland Tumours: United Kingdom National Multidisciplinary Guidelines. J Laryngol Otol 2016;130:S142–9. doi:10.1017/S0022215116000566.
- Terhaard CHJ, Lubsen H, Rasch CRN, Levendag PC, Kaanders HHÀM, Tjho-Heslinga RE, et al. The role of radiotherapy in the treatment of malignant salivary gland tumors. Int J Radiat Oncol 2005;61:103–11. doi:10.1016/j.ijrobp.2004.03.018
- Lagha A, Chraiet N, Ayadi M, Krimi S, Allani B, Rifi H, et al. Systemic therapy in the management of metastatic or advanced salivary gland cancers. Oral Oncol 2012;48:948–57. doi:10.1016/j.oraloncology.2012.05.004
- http://www.clinicaltrials.gov n.d.
