Q1. B
Q2. D
Q3. C

Pulmonary hyalinizing clear cell carcinoma of salivary gland type.

The tumor is lobulated and relatively well circumscribed. It is composed of solid nests, trabeculae, and cords of neoplastic cells (Figure 2, contoured/hollow arrow, short black arrow, and long black arrow, respectively) immersed in a stroma that varies from loose connective tissue (Figure 2, star) with some inflammation, to extensive hyalinizing fibrosis (Figure 2, asterisk, and Figure 3). The tumor cells consist of a combination of polygonal to round cells with pale to eosinophilic cytoplasm, and clear cells (Figure 4, short arrow and long arrow, respectively). Scattered glands are also present (Figure 4, contoured/hollow arrow). There is minimal cytologic atypia, and mitoses are not easily found. The tumor cells are diffusely immunoreactive to p40 (Figure 5) and negative for TTF-1. Entrapped alveolar pneumocytes are positive for TTF-1 (Figure 5, arrows), while the glandular structures in the midst of the lesion are negative (not shown). FISH for EWSR1 using a break apart probe, is positive (i.e., split signals are present).

Hyalinizing clear cell carcinoma (HCCC) is a rare low grade carcinoma of the head and neck, classically arising from the minor salivary glands. HCCC primary to the lung arising from the bronchial glands is extremely rare, as only 10 cases have been reported, five occurring in men and 5 in women. The patients’ ages ranged from 32 to 59 years old. Smoking history was provided for 7 patients, of whom 5 were smokers or former smokers. Pulmonary HCCC has similar morphologic features to its counterpart in the head and neck, and both also share the immunohistochemical and molecular profile. Head and neck HCCCs have an overall relatively good prognosis, with delayed local recurrences occurring in 10 to 20% of the cases. Rare cases with late distant metastases have been reported. All but one of the pulmonary cases did not have evidence of recurrence during follow-up periods that ranged from 10 to 181 months. In one case, the diagnosis of HCCC was made retrospectively on the resections of the recurrent lesions of a lung tumor that had been resected and diagnosed as squamous cell carcinoma 16 years prior.

Immunophenotypically, HCCCs show squamous differentiation, as they are consistently immunoreactive to cytokeratin 34βE12, p40, p63, and cytokeratin 5/6. The clear cells show PAS/PAS-D staining consistent with intracytoplasmic glycogen. HCCCs of the head and neck, and all reported pulmonary cases, show EWSR1-ATF1 rearrangements.

In view of the rarity of primary pulmonary HCCC and its histologic heterogeneity, this type of salivary gland tumor may not be easy to recognize. Differential diagnoses include squamous cell carcinoma with clear cell features, mucoepidermoid carcinoma with paucity of mucous cells, myoepithelial or epithelial-myoepithelial neoplasms, and clear cell carcinomas metastatic from extrathoracic sites, such as renal cell carcinoma. Differentiating HCCC from squamous cell carcinoma or mucoepidermoid carcinoma may be challenging, as they share squamoid morphology and squamous immunoprofile. Glands present in HCCC may mimic entrapped alveolar cells of a squamous cell carcinoma. Furthermore, mucous cells are not infrequently seen in HCCC. Therefore, recognition of the architecture and stromal characteristics of HCCCs is helpful to entertain this possibility in the differential diagnosis. The identification of the EWSR1 translocation with break-apart FISH, and absence of MAML2 rearrangements confirm the diagnosis of HCCC. Other differential diagnoses include myoepithelial and epithelial-myoepithelial tumors, which may be excluded with immunohistochemical stains, since HCCCs are negative for myoepithelial markers S-100, muscle-specific actin, smooth muscle actin, SOX 10 and calponin. Metastases from other sites should also be excluded using site-specific immunohistochemical stains. Last but not least, it is important to obtain a thorough clinical history to rule out metastatic HCCC from a previous head and neck primary.

Take home message: An unusual architectural pattern and prominent hyalinized fibrous stroma in a carcinoma with squamous differentiation are key features facilitating recognition of pulmonary hyalinizing clear cell carcinoma.

Albergotti WG, Bilodeau EA, Byrd JK, et al. Hyalinizing clear cell carcinoma of the head and neck: Case series and update. Head & Neck 2016;38:426-433.

Jeffus SK, Gardner JM, Steliga MA, et al. Hyalinizing clear cell carcinoma of the lung: case report and review of the literature. Am J Clin Pathol 2017;148:73-80.

Takamatsu M, Sato Y, Muto M, et al. Hyalinizing clear cell carcinoma of the bronchial glands: presentation of three cases and pathological comparisons with salivary gland counterparts and bronchial mucoepidermoid carcinomas. Mod Pathol 2018;31:923-33.

Valeria Arrossi, MD
Assistant Professor
Pulmonary Pathologist
Department of Pathology
Cleveland Clinic, Cleveland OH