Mucoepidermoid Carcinoma in a 33-Year-Old White Man

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1 Mucoepidermoid Carcinoma in a 33-Year-Old White Man Christina M. Behring, DDS, 1 Michael A. Lazzari, DHEd, MS, MLS(ASCP) CM2 Lab Med Fall 2015;46: DOI: /LMD9RI33QNRSXNMM ABSTRACT Patient Demographics: A 33-year-old white man. Chief Complaint: Longstanding bump on the roof of the mouth. Treatment: The patient was referred to an oral maxillofacial surgeon for a pathology consultation. The patient had been experiencing pain on both sides of his jaw, but the oral mass was not painful (Image 1). Medical History: The patient has no history of smoking, is slightly overweight with a body mass index of 26.5, and has no systemic or chronic medical conditions. Examination Findings: On initial examination by the oral surgeon, the vital signs of the patient were normal. An indurated lesion was noted on the left hard palate of the patient. Suspecting a benign lesion or possible carcinoma/neoplasm, the oral surgeon scheduled and performed an excisional biopsy (Image 2). The mass was sent for pathological processing. Postoperative Care: This included a diet of soft foods, with daily rinsing using 0.12% chlorhexidine gluconate, with a follow-up appointment made for 2 weeks later. Principal Laboratory Findings: Figure 1; Image 3; Image 4 Keywords: mucoepidermoid carcinoma, MECT1-MAML2, salivarygland neoplasm Questions 1. What clinical and laboratory findings are most striking? 2. What is the differential and most likely diagnosis in this patient? 3. What are the major causes of this disease? 4. What tests are used to confirm this diagnosis? Abbreviations MEC, mucoepidermoid carcinoma; CMV, cytomegalovirus; HPV, human papillomavirus; MRI, magnetic resonance imaging; CT, computed tomography; PET, positron emission tomography; FNA, fine-needle aspiration; FISH, fluorescent in situ hybridization; RT-PCR, reversetranscription polymerase chain reaction 1 Private Practice, Sanford, MI, US, 2 Department of Microbiology, University of Wisconsin La Crosse *To whom correspondence should be addressed. mlazzari@uwlax.edu 5. What is the frequency of this disease in the general population? 6. What are the treatment options and management possibilities for this disease? Possible Answers 1. When considering a diagnosis for the patient, noted clinical features included his age, sex, and medical history, particularly his longstanding abstinence from tobacco use. Location of the mass is key, while noting its presentation of induration and the lack of pain experienced by the patient. Important laboratory findings include the presence of mucous, epithelial, and epidermoid cells, as well as positive results via mucicarmine staining (Image 5). 2. Based on the clinical history and presentation of this specific patient, the differential diagnoses are listed in Figure 2. The most likely diagnosis in this patient is salivary gland cancer specifically, mucoepidermoid Downloaded from Fall 2015 Volume 46, Number 4 Lab Medicine 327

2 Image 1 Initial presentation of left hard palate mass. Image 2 Biopsy of left hard palate mass. carcinoma (MEC). MEC treatment and prognosis are based on the TNM stage and grade of the cancer. Stage is determined based on the characteristics of the primary tumor (location, size, depth of growth at its origin, and growth into nearby tissue), its spread to nearby lymph nodes, and whether the cancer has metastasized. Grading of MEC is determined microscopically by measuring the appearance of abnormal cancer cells. MECs can be found at different grades, ranging from low to high grade, with the latter having a worse prognosis. At each grade of MEC, this cancer can mimic other diseases and needs to be differentiated from other similar malignant conditions. For low-grade MECs, one must rule out Warthin tumors, benign salivary gland cysts, branchialcleft cysts, sialothiasis, and pleomorphic adenoma with excess mucoid stroma. High-grade MECs should be differentiated from squamous-cell carcinoma, salivaryduct carcinoma, and adenocarcinoma. 1 MECs were first identified in 1945 and can involve 3 types of cells: squamous, mucus secreting, and intermediate cells. 2 MEC can develop with no signs or symptoms. The first indication may be determined after oral cancer screening by a dentist or during a physical examination by a physician. The tumor that develops is usually painless and grows slowly. Some tumors, however, grow quickly. The general symptoms of MECs include site tenderness, difficulty swallowing, ear discharge, and oral spasms. Tumors are generally less than 4 centimeters in diameter Although the exact cause of MEC is unknown, it is thought that major contributors for its development are age, ionizing radiation exposure, and possible exposure to certain chemicals. Other study results have reported a possible relationship with infection of cytomegalovirus (CMV) and human papillomavirus (HPV). 3,4 However, a recent study 5 provided no link between HPV and MEC with or without the MAML2 rearrangement. Although the presence of CMV and HPV has been shown in patients with MEC, there is no known indication of causation at this point. Image 3 Normal surface epithelium at the top. The central portion of the image shows MEC infiltrating though the lamina propria (hematoxylin-eosin staining, original magnification x40). 4. The tests used to diagnose MEC include a physical examination with patient history, magnetic resonance imaging (MRI), computed tomography (CT) scan, positron emission tomography (PET) scan, endoscopy, and/ or biopsy. The type of biopsy can include fine needle aspiration (FNA), excisional biopsy, or biopsy via surgical Downloaded from Lab Medicine Fall 2015 Volume 46, Number 4

3 Case Studies Image 4 Image 5 Solid epidermoid and intermediate cells, as well as occasional mucous cells (hematoxylin-eosin staining, original magnification x200). Intracytoplasmic mucin is shown as bright pink on the slide (hematoxylin-eosin staining, original magnification x200) Table 1. Mucoepidermal Carcinoma (MEC) Grades Grade Cellular Composition Cell Differentiation 5-Year Survival Rate Low Intermediate High Mucus secreting and intermediate cells, possible goblet cells Mixture Squamous epithelial and intermediate cells Well-differentiated Intermediate Poor differentiation 92%-100% 62%-92% 0-43% procedure.6 The standard for initial diagnosis is through preoperative FNA. The FNA will aid in obtaining a specific diagnosis or will significantly reduce the possibilities in the differential diagnosis, which ultimately aids in the surgical approach. During pathological processing, mucicarmine staining by a pathologist can be used to help differentiate MEC from squamous-cell carcinoma. At time of diagnosis, it is also important to determine the cancer stage and whether the cancer has spread to other locations in the body. Determining the tumor grade is important because the overall likelihood of successful treatment and survival correlates with the severity of the neoplasm. Table 1 shows how the different MEC grades are determined and outlines the overall 5-year survival rate for each grade.1,7 Overall prognosis depends on the tumor staging, location, and grading, as well as the likelihood of surgical success.2 It has been shown that patients with MEC possess a MECT1-MAML2 gene rearrangement [t(11;19)(q1421;p12-130]. This translocation has been shown8 to occur in all grades of MECs and only in MECs. This translocation is identified using fluorescent in situ hybridization (FISH) or using reverse-transcription polymerase chain reaction (RT-PCR). This gene rearrangement is believed to disrupt the Notch signaling pathway, which is important in the normal development of cells and tissues. This disruption likely contributes to the lack of control and development of a neoplasm.9,10 5. MEC is the most common type of malignant neoplasm of the salivary glands in adults, with most cases occurring in the parotid gland. MEC is more prevalent in women than men; the mean onset is generally Downloaded from Fall 2015 Volume 46, Number 4 Lab Medicine 329

4 Figure 1. Oral Pathology Report From Our Patient, A 33-Year-Old White Man Gross Description Source of specimen: left hard palate Specimen consists of an oval mucosal fragment, white mucosa, and central bulging area Microscopic Description Specimen shows presence of salivary-gland tumor composed of mucous, epithelial, and epidermoid cells Cells are arranged in ductal structures, proliferating from ductal lining Nuclei appear monomorphic and pyknotic Mucicarmine stain is positive for intracellular and extracellular mucin Tumor is well encapsulated, margins are free of tumor material Figure 2. Differential Diagnoses for Our Patient, A 33-Year-Old White Man 1. Blue nevi 2. Hamartoma 3. Polymorphous adenoma 4. Mucoepidermoid carcinoma 5. Adenoid cystic carcinoma 6. Polymorphous low-grade adenocarcinoma 7. Non-Hodgkin lymphoma 8. Kaposi sarcoma 9. Lymphangioma 10. Melanoma 11. Acinic cell carcinoma 12. Peripheral giant cell lesion (granuloma) 13. Angiosarcoma used in conjunction with operations to prevent the spread of the cancer. Once patients have been treated, they are routinely checked in the future for reoccurrence of cancer. Five-year survival rates are listed in Table 1. Patient Follow Up Image 6 The left hard palate following the second biopsy. approximately age 45 years. Although this disease is more common in middle-aged patients, MEC and acinic cell carcinoma are not uncommon in children and must be included in the differential diagnosis of salivary gland masses in children. 2 One study group 11 examined the frequency of MEC in its hospital facility and discovered that of 151 malignant salivary-gland tumors, 75 were MEC (49.6%). The average age of the patients with MEC was 42.6 years (range, 6 years to 67 years), with a distribution of 36 males and 39 females. Of the 75 cases, 29 were high grade, 10 were intermediate, and 36 were low grade Appropriate treatment and management depends on tumor grade, stage, clinical presentation, and location. The options for treatment include surgical procedures, radiation (fast neuron radiation or photon beam radiation therapy), and/or chemotherapy. 6 Surgical procedures are the most common type of treatment to remove tumors. As a tumor progresses from low grade to intermediate and high grades, radiation and chemotherapy are usually After the initial excisional biopsy, the patient returned to the oral surgeon 2 weeks later, stating that he had felt pain in the biopsy area for a week, but that the pain had subsided. On examination, the biopsy area showed signs of a recurring lesion, so a second biopsy was performed. No recurrence of malignant neoplasms was found on the second biopsy. A few months later, the site is slowly healing, with no signs of recurrence at this time (Image 6). Acknowledgments A special thank you to Richard Bartling, DDS, FRCD (c), for providing the information for this case study and to Brent Accurso, DDS, MPH, for helping obtain microscopic images. LM References 1. Mukunyadzi P. Review of fine-needle aspiration cytology of salivary gland neoplasms, with emphasis on differential diagnosis. Am J Clin Pathol. 2002;118:S100-S Sepúlveda I, Frelinghuysen M, Platin E, et al. Mandibular central mucoepidermoid carcinoma: A case report and review of the literature. Case Rep Oncol 2014;7: Downloaded from Lab Medicine Fall 2015 Volume 46, Number 4

5 3. Melnick M, Sedghizadeh PP, Allen CM, Jaskoll T. Human cytomegalovirus and mucoepidermoid carcinoma of salivary glands: Cell-specific localization of active viral and oncogenic signaling proteins is confirmatory of a causal relationship. Exp Mol Pathol. 2012;92: Isayeva T, Said-Al-Naief N, Ren Z, Li R, Gnepp D, Brandwein- Gensler M. Salivary mucoepidermoid carcinoma: Demonstration of transcriptionally active human papillomavirus 16/18. Head Neck Pathol. 2013;7: Bishop JA, Yonescu R, Batista D, et al. Mucoepidermoid carcinoma does not harbor transcriptionally active high risk human papillomavirus even in the absence of the MAML2 translocation. Head Neck Pathol. 2014;8: National Cancer Institute. PDQ Salivary Gland Cancer Treatment: General Information about Salivary Gland Cancer. National Cancer Institute Web site. Available at: treatment/salivarygland/patient. Accessed on: July 28, Pires FR, de Almeida OP, de Araújo VC, Kowalski LP. Prognostic factors in head and neck mucoepidermoid carcinoma. Arch Otolaryngol Head Surg. 2004;130: Seethala RR, Dacic S, Cieply K, Kelly LM, Nikiforova MN. A reappraisal of the MECT1/MAML2 translocation in salivary mucoepidermoid carcinomas. Am J Surg Pathol. 2010;34: Tonon G, Modi S, Wu L, et al. t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway. Nat Genet. 2003;33: Allenspach EJ, Maillard I, Aster JC, Pear WS. Notch signaling in cancer. Cancer Biol Ther. 2002;1: Qureshi SM, Janjua OS, Janjua SM. Mucoepidermoid carcinoma: A clinico-pathological review of 75 cases. Int J Oral Maxillofac Pathol. 2012;3:5-9. Downloaded from Fall 2015 Volume 46, Number 4 Lab Medicine 331

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