Salivary Gland-type Tumors of the Lung: A Distinct Group of Uncommon Lung Tumors

MEC is the most common pulmonary SGT, accounting for less than 0.5% of all lung cancers in adults but 9% to 18 % of malignant lung tumors in children.^5,7,18–20  These tumors may be encountered in any age group (3–78 years); however, approximately 50% of them occur in patients aged less than 30.¹⁵  There is a slight male predominance with male-to-female ratio 1.1:1 but no definitive association with smoking.^{8,13,16,21–23}  Based on the current World Health Organization classification of pulmonary tumors, MECs are subclassified into low-grade and high-grade tumors.²  Low-grade MEC generally has a favorable course, but high-grade tumors behave similarly to other non–small cell carcinomas.^8,16,19,24 

Microscopically, MECs consist of mucin-secreting cells (mucocytes), squamous cells (epidermoid cells), and intermediate-type cells in cystic and solid patterns. Cystic spaces are lined by bland mucocytes with spilled mucus and solid component is comprised of squamous and intermediate cells. More than 80% of MECs of the lung are classified as low-grade tumors,^4,10  which are characterized by mixed cystic and solid areas, minimal cytologic atypia, low mitotic activity, lack of lung parenchyma infiltration, and absence of necrosis (Figure 1, A and B). High-grade MECs mainly consist of epidermoid and intermediate cells in solid growth pattern with significant cytologic atypia, greater than 4 mitoses/10 HPF, and frequent necrosis.^1,4,24–26  Features helpful in distinguishing high-grade MEC from other lung cancers, such as adenosquamous carcinoma, squamous cell carcinoma, and adenocarcinoma, include central/endobronchial or peribronchial location, presence of mucous cells, lack of keratinization and squamous pearl formation, surface epithelium lacking squamous carcinoma in situ, and transitional areas to low-grade MEC.¹⁰ 

MEC usually shows variable degree of positive staining for cytokeratin 7 and cytokeratin 5/6.²⁷  P63 and p40 also shows nuclear positivity in neoplastic cells. Mucicarmine stain is positive in intracytoplasmic or extracellular mucin material. Ki-67 can be helpful in identifying areas with high-grade features.²⁸  HER2 has been described in MEC of salivary gland with high-grade features, but no HER2 staining was noted in pulmonary MEC.^28,29  Immunohistochemical markers of lung origin like TTF-1 and Napsin A are negative.²⁸  The majority of pulmonary MEC cases (76%–89%) show rearrangement of MAML2 (Mastermind-like gene 2) gene.^21,30  This molecular alteration is often a result of t(11;19)(q21;p13) chromosomal translocation involving CRTC1 (CREB-regulated transcription coactivator 1 [CRTC1, previously referred to as MECT1—mucoepidermoid carcinoma translocated 1]) and MAML2 genes although t(11;15)(q21;q26) chromosomal abnormality with CRTC3-MAML2 gene fusion has been reported in a small portion of salivary gland MECs.^21,31 

AdCC is generally a slow growing neoplasm with high risk for recurrence, representing 0.2% of all primary lung neoplasms.¹  Patients range from 18 to 90 years in age (median 60), showing no sex predominance and no smoking association.^9,16,32  Patients with AdCC are reported to have similar or slightly poorer prognosis than those with MEC but better prognosis than those with non–small cell carcinoma.^{8,16,17,32–34} 

The histologic features of pulmonary AdCCs resemble their analogous tumors of the salivary glands, characterized by cribriform, tubular, and solid patterns with myxoid and hyaline material (Figure 1, C and D). Some tumors form tubular structures that comprise inner luminal cells and outer myoepithelial cells with stromal material in the lumen. The tumor cells are small sized with scant cytoplasm and hyperchromatic nuclei. Submucosal spread and perineural invasion are frequently seen. Poor prognosis is related to the proportion of solid growth, stage of the tumor, and positive resection margins. The differential diagnosis includes neuroendocrine tumor and basaloid squamous cell carcinoma.

AdCC usually shows positive staining for cytokeratin 7, p63, p40, S100, calponin, and CD117. P63 expression pattern is unique in AdCC as it shows nuclear peripheral staining or if the architecture is cribriform then nuclear staining in the internal luminal cells.³⁵  Approximately 41% to 58% of pulmonary AdCCs have MYB (v-myb avian MYB viral oncogene homology) gene rearrangement as a result of t(6;9)(q22-23;p23-24) chromosomal translocation resulting in MYB-NFIB (nuclear factor IB) gene fusion.^36–38  The remainder cases may show t(8;9)(q13;p22) chromosomal translocation with MYBL1-NFIB gene fusion.³⁷ 

EMC is a low-grade malignancy and rarely involves the lung. Currently, there have been less than 60 cases of pulmonary EMCs reported in the English literature.³⁹  The patient age of the reported cases ranges from 7 to 81 years, with an average of 56 years. There is slight male predilection, with male-to-female ratio 1.3:1, but no association with smoking. The majority of the tumors are located in the central airway.^39–41  Most pulmonary EMCs behave indolently, although recurrence and metastasis may occur in approximately 10% of cases.^39,42–44 

EMC is characterized by duct-like structures with biphasic appearance, consisting of an inner layer of epithelial cells and an outer layer of myoepithelial cells (Figure 1, E and F). Myoepithelial cells are spindle, plasmacytoid, and clear in appearance and are sometimes arranged in a solid pattern, even to the extent of dominating the epithelial component.

These tumors are positive for pancytokeratin, cytokeratin 7, and cytokeratin 5/6. Neoplastic myoepithelial cells are positive for calponin, p63, smooth muscle actin, and S100. TTF-1 is usually negative although TTF-1 positivity has been previously reported in epithelial cells.^41,44  Pneumocytic adenomyoepithelioma, characterized by TTF-1 expression, is considered as a variant of EMC,⁴²  but the recent study has shown that TTF-1 positive cells are entrapped pneumocytes.⁴⁵  CD117 can be positive in the myoepithelial component of EMC.

Although PA is the most common tumor of the salivary glands of head and neck area, it rarely occurs in the lung. There are less than 50 reported cases so far, with the age of the patients ranging from 26 to 76 and without evident sex predominance.^43,46–50  Although PA is usually a benign tumor with a good prognosis, in rare cases a tumor may recur and metastasize and can even behave as low-grade malignant carcinoma.^50,51  Additionally, carcinoma can arise in the background of PA, as known as carcinoma ex pleomorphic adenoma.

PA comprises epithelial, myoepithelial, and stromal components, characterized by cords, tubules, ducts, and nests embedded in or merging with a myxoid or chondromyxoid stroma (Figure 2, A and B). Solid sheets of myoepithelial cells with spindle, clear, or plasmacytoid appearance are a common finding. PA may also have focal areas of squamous differentiation along with keratinization, a condition that needs to be differentiated from squamous cell carcinoma. Presence of well-formed cartilage is uncommon in pulmonary PA.^1,4,43 

PA is a biphasic tumor with epithelial and myoepithelial component that stains positive for cytokeratins, p63, S100, GFAP, calponin, and smooth muscle actin. At the molecular level, PAs are associated with chromosome 8q12 abnormality resulting in PLAG1 (pleomorphic adenoma gene 1) gene rearrangement and PLAG1 overexpression.^52,53 PLAG1 gene rearrangement has also been reported in pulmonary PA.⁴⁷ 

HCCC is extremely rare in the lung. There are less than 10 reported cases in the English literature.^54–59  No sex predominance is observed, and the reported patient age ranges from 32 to 55. Based on the limited data, pulmonary HCCC behaves like a low-grade carcinoma with good prognosis, but very rarely lymph node metastases can occur, warranting long-term surveillance.^60,61 

Similar to its counterpart in the salivary glands, pulmonary HCCC is characterized by hyalinized or sclerotic stroma and monotonous epithelial cells arranged in nest, cord, and trabeculate patterns (Figure 2, C and D). The epithelial cells are small to medium in size, containing glycogen rich clear or/and eosinophilic cytoplasm with irregular nuclei. Given the rarity of this tumor, it is essential to exclude a metastatic salivary gland HCCC before establishing diagnosis of primary HCCC of the lung.

HCCC is usually positive for pancytokeratin, cytokeratin 7, p40, and p63 while negative for S100, TTF-1, and Napsin A.^4,58  The most important diagnostic feature is t(12;22)(q13;q12) chromosomal translocation with EWSR1-ATF1 (Ewing sarcoma breakpoint region 1-activating transcription factor1) gene fusion.^58,62 

MGA originates from the seromucinous glands and ducts of tracheobronchial tree. Of the reported cases, the patient age ranges from 7 to 67, with a mean of 52 years in 1 study and 26 years in another.^63,64  Males and females are equally affected. The majority are found in the central airway, but cases with parenchymal involvement unrelated to the airway have also been reported.^63–66  As a benign tumor, mucous gland adenoma has an excellent prognosis.

The tumor is confined to submucosa without extension beyond cartilage plate, showing a mixture of mucin-filled dilated cysts, glands, tubules, ducts, and papillary fronts surrounded by scattered myoepithelial cells (Figure 2, E and F). Large cysts may be lined with flattered to cuboidal epithelial cells; glands, tubules, and ducts are lined by columnar epithelial cells with apical mucin and basally located nuclei; papillary formation is usually a minor component.

MGA is usually positive for cytokeratins but negative for TTF-1 and Napsin A.⁶⁷  Calponin, p63, or S100 highlights myoepithelial cells at the peripheral of epithelial structures.

Pulmonary SGTs are rare and oftentimes poses diagnostic challenges, especially in small biopsy samples. Most of these tumors are located centrally and usually subjected to bronchoscopy evaluation with either endobronchial biopsy, fine-needle aspiration, or bronchial brushing. Diagnostic challenges in these small biopsy specimens are related to limited sampling, overlapping features among pulmonary SGTs as well as other lung tumors, and presence of benign native minor salivary gland tissue in the bronchopulmonary tissue. The scenarios that can come across while evaluating limited bronchial samples include nondiagnostic (not representative of the lesion of interest), atypical (very limited samples insufficient for further workup), suspicious, or positive but difficult to diagnose or classify into a particular category based on morphologic features.

Nondiagnostic or atypical cases should be managed with a follow-up repeat biopsy procedure. However, the cases with suspicious or positive diagnosis can be further worked up by using ancillary testing, such as immunohistochemistry or/and molecular analysis. Cases with concern for MEC should be evaluated for MAML2 gene rearrangement. Similarly, cases with AdCC-like morphology can be confirmed by MYB or MYBL1 gene alteration, and identification of EWSR1-ATF1 fusion is supportive of diagnosis of HCCC. Cases without any particular molecular alterations are challenging on limited samples. Identifying epithelial and myoepithelial components by immunohistochemistry is helpful for biphasic tumors but these tumors may be difficult to be precisely classified. Correlation with clinical and imaging features and providing a descriptive diagnosis with a note explaining differential diagnosis would be helpful. Nevertheless, it is advised to use the term “non–small cell carcinoma with features suggestive of salivary gland-type tumor” as recommended unless the morphology is typical and a specific molecular alteration is identified.²  An exception to use this terminology is benign tumors, such as MGA.

Primary SGTs of the lung have to first be differentiated from metastatic salivary gland tumors. The distinction between these 2 entities is challenging as they share the same morphologic, immunohistochemical, and molecular features. Clinical features including imaging findings and prior history of extrapulmonary salivary gland tumor are helpful. It is worth noting that SGTs from head and neck region differ greatly in the incidences of individual tumors from pulmonary SGTs. PA is the most common SGT while MEC is the most common malignancy in the head and neck area.⁶⁸  Distant metastasis is seen in 15% to 20% of head and neck SGTs with the lung being the most common site of distant metastases.^69–71  Among the metastatic SGTs, AdCC is the most common type.⁶⁹  The differential diagnoses of pulmonary SGTs from other lung tumors are detailed in the Table.

Low-grade MEC of the lung can mimic MGA or adenocarcinoma with mucinous features or mucinous adenocarcinoma. Identifying 3 morphologic components (mucous cells, intermediate cells and epidermoid cells [squamous cells]) would be helpful for the diagnosis of low-grade MEC. The differential diagnosis for high-grade MEC includes adenosquamous carcinoma, squamous cell carcinoma, or salivary duct-type carcinoma. Keratin pearls formation or marked pleomorphisms is usually not seen in MEC. Adenosquamous carcinoma are usually periphery located and may show 2 components (squamous component-p40 positive and adenocarcinoma-mostly TTF-1 positive) (Figure 3, A and B). An in situ component may be seen in the adjacent airway epithelium. MEC is centrally located and morphologically has an intermediate cell component in addition to mucous and squamous cells and may show MAML2 molecular alteration. However, this particular molecular alteration is more frequently seen in low-grade tumors.²¹ 

AdCC has classic cribriform morphology with hyaline matrix, which can also be seen in other tumors, such as basaloid squamous cell carcinoma (SqCC) (Figure 3, C and D), adenocarcinoma, and neuroendocrine tumor. P63 and p40 immunostainings are usually patchy and weak as compared with strong and diffuse positivity in basaloid SCC. Basaloid SqCC usually show increased mitosis and high proliferation rate by using Ki-67. Presence of MYB or MYBL1 gene rearrangement helps diagnosis of AdCC. Negative neuroendocrine markers help differentiation of AdCC from neuroendocrine tumors.

EMC is a low-grade malignancy and morphologically should be differentiated from PA, AdCC, low-grade MEC, and perivascular epithelioid cell tumor. Both EMC and PA have biphasic cell proliferation; however, EMC often has tubular structures which is bilayered with an inner layer of epithelial cells (positive epithelial marker, ie, cytokeratin) and outer layer of myoepithelial cells (positive myoepithelial markers, ie, p63). If EMC shows clear cell changes, it may be confused with MEC but the latter usually shows mixed squamous cells, intermediate cells, and mucous cells and has a characteristic molecular alteration. AdCC can show similar immunohistochemical features (such as expression of p63 and cytokeratins) but morphologic features of AdCC (cribriform) are different from EMC (bilayered pattern). A perivascular epithelioid cell tumor (clear cell tumor) can show some morphologic overlapping features with EMC with clear cell features but unlike EMC, a perivascular epithelioid cell tumor is positive for HMB45 and Melan-A.

Differential diagnosis of PA includes hamartoma, pulmonary blastoma, EMC, AdCC, and carcinosarcoma. Hamartoma usually shows epithelial proliferation with chondroid or myxoid matrix. LPP-HMGA2 gene fusion, if present, would be helpful to differentiate hamartoma from its morphologic mimickers.⁷²  Pulmonary blastoma has biphasic morphology with low-grade epithelial component and hyperchromatic blastematous mesenchymal component. Pulmonary blastoma may have morule formation associated with aberrant nuclear/cytoplasmic beta-catenin expression.^73,74  EMC has its peculiar morphologic pattern of epithelial and mesenchymal cells in bilayered pattern. AdCC can show overlapping features with PA but PA has chondromyxoid matrix and shows a biphasic cell population and lacks stromal infiltration.

HCCC can morphologically mimic other tumors like MEC, EMC, metastatic clear cell renal cell carcinoma, and perivascular epithelioid cell tumor (clear cell tumor). HCCC shows a distinctive EWSR1 translocation that is not seen in other differential diagnosis entities. Metastatic clear cell renal cell carcinoma is positive for PAX-8, CD10, and CA-IX.

The differential diagnosis of MGA includes low-grade MEC and adenocarcinoma with mucinous features. MGA is a benign tumor and lacks infiltrative growth. MEC typically shows MAML2 rearrangement. An early stage of mucinous adenocarcinoma may not exhibit an obvious infiltrating pattern but lacks p63 expression.

Pulmonary SGTs are clinically and prognostically different from conventional lung carcinomas, despite some overlapping morphologic features. Many pulmonary SGTs have specific diagnostic molecular alterations while others have either characteristic morphologic or/and immunophenotypic features. Pulmonary SGTs should be differentiated from its morphologic mimickers by combining the use of clinical history, imaging findings, histopathologic features, and ancillary testing.