Pediatric Pathology

Pleomorphic Adenoma of the Lung

Sara O. Vargas
Children's Hospital
Boston, MA


Clinical summary:
This 9-year-old boy had an incidentally discovered lung mass. He had been a healthy active child, and one day while swimming in a pool he came up for air directly in front of a chlorine jet. This caused him to cough and feel as though his throat was closing, and soon thereafter his parents brought him to his pediatrician. At this visit, the patient appeared well, and physical examination was unremarkable. A chest radiograph showed a left intrathoracic mass. A CT scan better defined the lesion as a left upper lobe peripheral heterogeneous mass measuring 4.0 x 3.8 x 3.6 cm; enlarged mediastinal lymph nodes were also seen.

The patient lived in a suburban Midwestern environment and had no significant travel history. His parents, a lawyer and a restauranteur, were nonsmokers. There was no family history of cancer.

A needle biopsy of the pulmonary mass was interpreted as showing malignancy. A week later, the patient underwent thoracoscopic resection of the lingular mass and a mediastinal lymph node.


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Pathologic findings:
Grossly, the lung contained a well circumscribed and slightly cystic tan mass (4.1 x 3.8 x 2 cm). Microscopically, the mass was vaguely lobulated and consisted of a variety of cell types within an abundant myxohyaline matrix. The cells were spindled to stellate in some areas and epithelioid in others. They formed nests and cords and frequently lined small spaces. Pleomorphism was minimal, and there was no mitotic activity. The matrix was pale and myxoid, and it merged with areas of cartilaginous differentiation. Additional cystic spaces were lined by pseudostratified respiratory epithelium. The same components were present within the mediastinal lymph node. The tumor showed diffuse staining for S100, GFAP, and NSE in myoepithelial and cartilaginous elements, as well as focal staining for pankeratin, EMA, and muscle-specific actin.

A separately submitted mediastinal lymph node was enlarged (3 cm) and contained tumor microscopically.

Diagnosis:
Pleomorphic adenoma of the lung.

Follow-up:
A CT scan of the head and neck revealed no salivary gland masses. The patient's family opted for no further therapy. The patient was well without recurrence 7 months after diagnosis.

Comment:
The lesion presented herein is a primary salivary gland-type neoplasm of the lung with features of pleomorphic adenoma and myoepithelioma. The distinction between these two entities can be subjective, as will be discussed below, and both are generally indolent but may exhibit malignant behavior. Those who interpret the lesion's presence within a lymph node to imply an aggressive biologic potential may prefer the term myoepithelial carcinoma or myoepithelial carcinoma ex pleomorphic adenoma, other distinctions that may be semantic since the terms pleomorphic adenoma and myoepithelioma already indicate the possibility of malignant behavior in a small subset of histologically "benign" cases.

Salivary gland-type tumors of the lung are uncommon but represent a substantial fraction of primary lung neoplasms in the pediatric population. They are thought to arise from bronchial mucosal glands and are most often central, although they may be peripheral as noted in this child.

Primary salivary gland-type neoplasms are many times more common in the head and neck than in the lung, and it is prudent to ascribe the primary site to lung only after clinically excluding a tumor in the head and neck. The histologic classification and grading schemes for salivary gland-type tumors have evolved based on the study of head and neck lesions. However, the prognostic importance of the histologic types and grades are less well studied in the lung. For pediatric patients with primary pulmonary salivary gland-type tumors, published data is even sparser.

In the lower respiratory tract, the most common primary salivary gland-type neoplasms are mucoepidermoid carcinoma and adenoid cystic carcinoma in both children and adults. This case of pleomorphic adenoma of the lung was selected for presentation not only for its rarity, but also because it presents a particularly interesting histologic differential diagnosis in the pediatric population and because it provokes consideration of new and controversial concepts with respect to pediatric myoepithelial cell-rich neoplasms of all sites.

Among primary intrathoracic neoplasms, the differential diagnosis for a solid and cystic cartilage-containing neoplasm includes pleuropulmonary blastoma (PPB). In fact, this case was diagnosed as PPB at the originating institution, illustrating this difficulty. PPB is an aggressive lung neoplasm of childhood that can consist of epithelial and mesenchymal elements. The epithelial elements are thought to be benign entrapped and variably metaplastic lung epithelium. The mesenchymal components consist of primitive blastema-like tissue often with cartilaginous and rhabdomyosarcomatous differentiation. Foci mimicking fibrosarcoma and other malignant tumors may be seen. In partly or fully solid tumors, anaplasia is a common finding. The partly or fully solid tumors are associated with less than 50% 5-year survival. PPB is associated with a high rate of familial tumors, including PPB, cystic nephroma, medulloblastoma, testicular germ cell tumors, and embryonal rhabdomyosarcoma; these may also occur as second malignancies in a subset of PPB patients. Because of the high rate of familial disease, genetic linkage studies, which are underway, are likely to reveal the involved gene. This promises to be an important breakthrough in the field of pediatric neoplasia, since so many different types of childhood tumors have been associated with "PPB family cancer syndrome."

A very rare neonatal cystic and solid lesion with cartilagenous differentiation, epithelium-lined cysts, and fibrous septa has been described as "chondroid cystic malformation of the lung." This lesion is described at the level of case reports only; it resembles the benign end of the spectrum of cystic ("type 1") PPB and shares with it the cytogenetic finding of trisomy 8; however, it lacks the primitive mesenchymal component characteristic of PPB and the frankly sarcomatous components that may be seen in PPB.

Another lesion in the differential diagnosis of a pediatric solid and cystic thoracic neoplasm containing poorly differentiated cartilage is chest wall hamartoma of infancy, although the clinical features of this tumor that develops in utero and involves the rib cage differ significantly from the clinical scenario for the patient presented herein. Chest wall hamartoma of infancy includes has cystic and solid components including cartilaginous differentiation. The solid components consist of a mixture of hyaline cartilage that merges with more mononuclear cells that have been described as "chondroblastoma-like." Unlike the cysts in pleomorphic adenoma/myoepithelima, which are epithelium-lined, the cystic component of chest wall hamartoma of infancy is a histologic mimic of aneurysmal bone cyst. Chest wall hamartoma of infancy can be cured by resection, and some have regressed spontaneously.

Carcinosarcoma is an "adult" tumor that might be considered in the histologic differential diagnosis. This was emphasized when another consultant rendered a diagnosis of carcinosarcoma on the patient presented here, noting the biphasic epithelial and mesenchymal differentiation and the presence of tumor within a lymph node. The term carcinosarcoma is better reserved for a type of bronchogenic carcinoma, most common in adult smokers, with clearly malignant features including an epithelial component of conventional nonsmall cell lung carcinoma. Clinical behavior is aggressive, with a worse prognosis than conventional nonsmall cell lung carcinoma. In the case presented herein, the ductal differentiation and clear resemblance to neoplasms found in the salivary gland, along with the myoepithelial immunophenotype, is convincing evidence of salivary gland-type differentiation.

Perhaps the most difficult and controversial differential diagnosis is with other myoepithelial-cell-rich neoplasms. With respect to salivary gland lesions, practice varies as to when to use the term "myoepithelioma" instead of pleomorphic adenoma. There are differences of opinion regarding the amount of cartilaginous differentiation (and what degree of myxochondroid differentiation constitutes "cartilage") and the amount of ductal differentiation permissible in myoepithelioma, making the distinction arbitrary. In myoepithelial-cell-rich tumors, the myoepithelial cells may be immunopositive for keratins, S100, EMA, GFAP, calponin, smooth muscle actin, desmin, p63, and desmin; for a confident diagnosis, positivity for at least one epithelial marker in addition to S100 or GFAP may be helpful.

In the head and neck, pleomorphic adenomas are often associated with rearrangements in the PLAG-1 gene on chromosome 8, in which case they may show immunopositivity for the PLAG1 protein. Other pleomorphic adenomas have shown rearrangements in the HMGA2 gene on chromosome 12. Cytogenetic findings in cases reported as myoepitheliomas and myoepithelial carcinomas are less common but include a chromosome 12 rearrangement in a parotid myoepithelioma and chromosome 8 alterations in head and neck myoepithelial carcinomas, suggesting a biologic overlap with pleomorphic adenoma.

The same issues of overlapping categorization apply for cutaneous appendageal tumors, in which "myoepithelioma" may encompass a variably broad category including pleomorphic adenoma/mixed tumor and chondroid syringoma, with some authors noting a morphologic continuum with eccrine and apocrine spiradenomas.

Soft tissue myoepithelioma has been increasingly recognized since the first report of a primary soft tissue myoepithelioma, occurring in the retroperitoneum, in 1995. In pediatric neoplasms, the term has been applied to an increasingly broad spectrum of tumors, with a wide range of histologic patterns but unified by the expression of "myoepithelial" markers, especially cytokeratin, EMA, S100, and GFAP. Morphologic patterns termed epithelioid, clear cell, plasmacytoid/rhabdoid, and spindle cell have been described. Using this framework, "parachordoma" becomes "myoepithelioma"; also a subset of lesions that might otherwise classically be viewed for example as rhabdoid tumor, chordoma, sarcoma NOS, etc., might tend to be subsumed by the rubric of "myoepithelioma." In fact, recent claims that soft tissue myoepithelioma may be INI-1 immunonegative illustrate this point, as do reports of EWSR1 gene rearrangements in soft tissue myoepithelioma.

In the case presented herein, the chondroid nodules, sclerotic nodules, and slitlike spaces lined by respiratory-type epithelium mimic pulmonary hamartoma to an extent. In the lung, there has been increasing recognition of the myoepithelial nature of pulmonary chondroid hamartoma, which has been found to contain many cells a with myoepithelial immunophenotype. Pulmonary hamartomas are characterized by clonal chromosomal rearrangements involving the HMGA1 and HMGA2 genes, supporting a biologic relationship to pleomorphic adenoma of the salivary glands and probably of the lung. The case presented herein also highlights the histomorphologic overlap between the tumors.

Another myoepithelial-cell-rich salivary gland-type neoplasm of the lung in the differential diagnosis of pleomorphic adenoma is mucoepidermoid carcinoma, which may have epithelium-lined cysts as a prominent component but which lacks myxochondroid differentiation. Epimyoepithelial carcinoma (also known as adenomyoepithelioma, epithelial-myoepithelial tumor of unknown malignant potential, and pneumocyte adenomyoepithelioma) is a salivary gland-type tumor with glandular structures as a prominent component; the glands are composed of two distinct layers, with an apical epithelial cell layer and a basal myoepithelial cell (clear cell) layer. Although pleomorphic adenoma may contain areas resembling epimyoepithelial carcinoma, it is distinguished by its morphologic heterogeneity.

A final category of disease that should be considered is metastatic disease. In pediatric patients there are a number of pleuripotent "blastomatous" neoplasms, such as hepatoblastoma and Wilms tumor, that may involve the lung and may exhibit mesenchymal and epithelial components with varying degrees of cytodifferentiation. In this setting the precise categorization of a very well-differentiated lesion as primary or metastatic may prove problematic without ancillary tumor genetic information. It also bears reiterating that consideration should be given to metastasis from a primary salivary gland tumor.

To summarize, the case presented herein is a primary pulmonary salivary gland-type tumor with features of pleomorphic adenoma. In the histologic differential diagnosis are other primary cartilage-containing lung neoplasms including PPB, carcinosarcoma, and pulmonary chondroid hamartoma. Pleomorphic adenoma may also resemble other myoepithelial-cell-rich primary lung salivary gland-type neoplasms; the distinction between pleomorphic adenoma and myoepithelioma or myoepithelial carcinoma may in many situations be arbitrary, while the distinction from mucoepidermoid carcinoma and epimyoepithelial carcinoma is clearer based on histomorphologic features. Myoepithelial cell neoplasms are an emerging and somewhat controversial concept and an increasingly diagnosed category of pediatric neoplastic disease, and the process of integrating this new outlook into the framework of our more well-established traditional disease categories is ongoing.

Acknowledgements
Presentation of this case would have been impossible without the efforts of Douglas Anthony, M.D., Ph.D., Chairman of the University of Missouri Pathology Department who provided the material and clinical information from his institution. Thanks to Larisa Debelenko, M.D., Ph.D. (St. Jude Children's Research Hospital, Memphis, TN) for performing PLAG1 immunostaining on the case. Thanks to subspecialists Scott Granter, M.D., Jason Hornick, M.D., Ph.D., Lucian Chirieac, M.D., and Jeff Krane, M.D., Ph.D. (Brigham and Women's Hospital, Boston, MA), for discussions about the viewpoints on myoepithlioma within their specialties and to Harry Kozakewich, M.D. and Antonio Perez-Atayde, M.D. for offering their perspectives. And special thanks to Stephen J. Qualman, M.D., and the Children's Oncology Group for the opportunity to review material from primary pediatric tumors archived in the Biopathology Center, Columbus, OH, from which a number of the slides photographed in the presentation are taken.

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