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August, 2020
Case of the Month

Clinical History: A 28-year-old man with progressively worsening dyspnea on exertion was noted on chest imaging to have a near-completely-obstructing endoluminal lesion in the distal trachea. He is a never smoker and endorsed no significant past medical history. Bronchoscopy confirmed the presence of a lobulated, partially-obstructing endotracheal lesion (Figure 1). A rigid bronchoscope was used to core out the lesion and electrocautery was applied to the base for tissue ablation and hemostasis. Histologic sections (Figures 2-5; H&E) demonstrated a circumscribed epithelial neoplasm composed of expansile nests of clear cells with only mild cytologic atypia. The clear cells were admixed peripherally with slightly larger-appearing cells characterized by eosinophilic cytoplasm and occasional small central nucleoli. Scattered throughout the tumor were collections of mucin-containing cells with occasional small cysts. A somewhat arborizing vascular network with some hyaline-appearing fibrosis was also present. Mitoses were not apparent and neither keratinization nor necrosis were identified. The over lying tracheal epithelium demonstrated early evidence of squamous metaplasia, but no overt cytologic atypia. Immunohistochemical stains (Figure 6) demonstrated the lesional cells to be diffusely CK7 positive with focal collections of cells demonstrating p40 and CK5/6 positivity. The lesional cells were TTF-1 negative.


Q1. Which of the following is true of this tumor?

  1. This tumor is more frequently seen in patients who endorse a history of tobacco smoking.
  2. About 50% of these tumors occur in individuals younger than 30 years of age.
  3. This tumor is more frequently seen in women.
  4. More often than not, this tumor carries a prognosis similar to other non-small cell lung cancers.

Q2. Which of the following ancillary tests would be most useful in confirming the diagnosis?

  1. Fluorescence in situ hybridization using probes targeted to the EWSR1 locus.
  2. Fluorescence in situ hybridization using probes targeted to the ALK locus.
  3. Fluorescence in situ hybridization using probes targeted to the MAML2 locus.
  4. EGFR mutational analysis by next generation sequencing.

Q3. The differential diagnosis for this case would reasonably include which of the following?

  1. Adenosquamous carcinoma
  2. Metastatic clear cell renal cell carcinoma
  3. Hyalinizing clear cell carcinoma
  4. PEComa
  5. All of the above

Answers to Quiz

Q1. B
Q2. C
Q3. E


Mucoepidermoid carcinoma


Pulmonary mucoepidermoid carcinoma (PMEC) is a salivary gland-type neoplasm that is composed of mucus cells, intermediate cells, and squamoid cells. Occasionally tumors have abundant clear cytoplasm, such as the current case, or, rarely, oncocytic change. PMEC is a rare lung tumor that accounts for less than 1% of non-small cell carcinomas. PMEC is one of the most frequent endoluminal lesions encountered in the pediatric population. There is not a significant gender predominance. Rare cases of PMEC with EGFR mutations or ALK rearrangements have been reported; though, smoking is not thought to play a role in tumorigenesis. Unlike tumors of the salivary gland, which are graded as low, intermediate, or high-grade; PMEC are currently graded as either low or high-grade according to the World Health Organization classification. Low-grade tumors lack significant cytologic atypia, necrosis, and mitoses. High-grade features, when present, are usually more appreciable among the squamoid cells. High-grade PMEC tend to have a more infiltrative growth pattern; though, it can be difficult to make an absolute distinction between high-grade PMEC and adenosquamous carcinoma, particularly on small biopsy. The presence of keratinization or keratin pearls would favor a diagnosis of adenosquamous carcinoma. Expression of TTF-1 would also favor a diagnosis of adenosquamous carcinoma. Adenosquamous carcinoma also tends to present more often as a peripheral lesion, whereas PMECs tend to be more central and endoluminal. The absence of squamous cell carcinoma in situ in the overlying airway epithelium and/or an abundance of intermediate cells would also favor high-grade PMEC over adenosquamous carcinoma..

The vast majority of recently published cases of PMEC harbor a recurrent t (11; 19) (q21; p13) translocation, resulting in a CRTC1-MAML2 fusion gene. In this case, fluorescence in-situ hybridization using probes to detect rearrangements of the MAML2 gene region was performed and reported as positive for rearrangement. Such rearrangements have been identified in both low and high-grade PMEC; though, their role as a prognostic indicator is not entirely clear. Immunohistochemically, PMECs are pancytokeratin, CK7, CK5/6, and p63/p40 positive. PMECs are TTF-1 and Napsin A negative. The presence of mucus cells and the MAML2 rearrangement effectively exclude the possibility of metastatic renal cell carcinoma. Hyalinizing clear cell carcinoma (HCCC) is also characterized by the presence of mucus cells; however, both salivary gland and pulmonary HCCC have been demonstrated to harbor EWSR1 rearrangements, not MAML2 rearrangements. Perivascular epithelioid cell neoplasms (PEComas) also lack MAML2 rearrangement and are generally positive for melanoma markers, smooth muscle actin, and desmin.

For this case, a final diagnosis of mucoepidermoid carcinoma, favor low-grade was rendered. Most PMECs are low-grade, and with complete surgical resection have an excellent prognosis. High-grade PMEC portends a prognosis similar to other non-small lung cancers. This patient subsequently underwent tracheal resection with lymph node dissection that revealed no residual disease or evidence of metastasis.


Roden AC, Garcia JJ, Wehrs RN, et al. Histopathologic, immunophenotypic and cytogenetic features of pulmonary mucoepidermoid carcinoma. Mod Pathol 2014;27:1479-88.

Salem A, Bell D, Sepesi B, et al. Clinicopathologic and genetic features of primary bronchopulmonary mucoepidermoid carcinoma: the MD Anderson Cancer Center experience and comprehensive review of the literature. Virchows Arch 2017;470:619-26.

Travis WD et al. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart, 4th Ed.


Scott W. Aesif, MD, PhD
Staff Pathologist
Department of Pathology
Cleveland Clinic
Cleveland, OH
2019 PPS Lifetime Achievement Award
Professor Elisabeth Brambilla
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