Cytopathology

Pleomorphic Adenoma

Barbara Ann Centeno
H. Lee Moffitt Cancer Center and Research Institute
Tampa, FL


Clinical History:
The patient was a 49 year old female, who was found to have a hard, irregular, mobile mass on physical examination of her right breast. The mass had recently increased to 4.5 cm in size and was associated with retraction of the overlying skin. Mammogram showed an oval mass with well-circumscribed borders and coarse, heterogenous calcifications in the subareolar region of the right breast. She had experienced a fall two to three months prior to presentation, which injured the right breast. Her past medical history was significant for invasive cervical cancer treated with chemotherapy and radiation 6 years prior to the discovery of this mass. A fine needle aspiration was performed using palpation. The patient subsequently underwent a central lumpectomy and sentinel lymph node biopsy.

Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
The fine needle aspiration smears were moderately cellular with groups of ductal-like cells in large sheets showing crowding, nuclear enlargement, anisonucleosis, and small, red, prominent nucleoli. These groups lacked breast myoepithelial cells. The background contained stroma that was purple on Diff-Quik and bluish on Papanicolaou. In some areas the stroma appeared dense and fibrillary, in other areas it appeared mucinous. Within the stromal material, single cells were noted, with bland nuclear features. Some of these cells had a plasmacytoid appearance. A cell block could not be performed but cytospins prepared from the needle rinsings contained clusters of cells also with crowding, anisonucleosis and subtle nuclear irregularities and small nucleoli. The lumpectomy specimen showed a 4.1 x 2.5 x 3.0 cm mass with well-defined borders, and a tan gray, granular and gritty surface. The tumor was 2.0 cm from the closest margin. The histopathology showed a well-defined tumor with epithelial and stromal components. The epithelial cells had a ductal morphology, and were arranged in large sheets. The cells had abundant eosinophilic cytoplasm. The nuclei ranged from round to oval, showed nuclear membrane irregularities, and nucleoli, which in some cells were prominent. The chromatin was slightly coarse. The stroma showed myxoid and chondroid differentiation and endochondral ossification. Within the mass was a large breast duct.


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Figure 1
Groups of ductal type epithelial cells with balls of myxoid material, Diff-Quik 40X
Figure 2
Dense, pinkish stroma with frayed edges Papanicolaou 40X
Figure 3
large sheet of ductal epithelium with crowding and overlapping, nuclear enlargement, anisonucleosis and adjacent myxoid stroma, Papanicolaou 40X
Figure 4
Enlarged atypical nuclei with nucleoli, Papanicolaou 60X

Figure 5
single plasmacytoid, and elongated spindled cells in dense myxoid stroma, Papanicolaou 40X
Figure 6
Cytospin showing group of cells with cytological atypia, Papanicolaou 60X
Figure 7
Low power image of resection specimen showing nests of epithelial cells in a Myxoid and chondroid matrix, H&E 4X
Figure 8
In areas, the chondroid matrix has undergone osseus metaplasia, H&E 4X

Figure 9
The neoplastic cells form tubules. The cells have abundant eosinophilic cytoplasm, anisonucleosis, variations in the nuclear membrane, and prominent nucleoli. H&E 40X.
Figure 10
Some areas of the neoplasm were more cellular. The nuclear and cytoplasmic features of the neoplastic cells are evident. The associated stroma is bubbly H&E 40X


Differential Diagnoses:
The cytological differential diagnoses may include: Primary breast carcinomas Mucinous carcinoma Metaplastic carcinoma Primary breast neoplasms with stroma Fibroadenoma or phyllodes tumor Papilloma with chondroid or metaplastic stroma Primary breast neoplasms with salivary gland morphology Pleomorphic adenoma Adenoid cystic carcinoma

Final Diagnosis:
Cytological diagnosis: mucinous carcinoma
Histopathological diagnosis: pleomorphic adenoma

Case Discussion:
This case of pleomorphic adenoma of the breast illustrates the challenges in correctly diagnosing this entity preoperatively, as the imaging and clinical findings may suggest malignancy, and it may be misdiagnosed both on cytopathology and frozen section, as both occurred in this case. In this case, the presence of cells with cytological atypia, the absence of breast myoepithelial cells, single cells, and the background material all suggested mucinous carcinoma. Complicating the picture is that mucinous carcinoma may also present as a well-circumscribed mass in the breast.

Retrospectively, this case showed two features which could have permitted the distinction of pleomorphic adenoma from mucinous carcinoma. The first feature is that there were stromal fragments showing the characteristic myxofibrillary appearance of pleomorphic adenoma. The second is that the cells appeared rigidly set within the associated myxoid substance rather than loosely floating.

A comparison of the staining qualities of the stroma in pleomorphic adenoma to those of mucinous carcinoma has shown that the mucin in pleomorphic adenoma will be lost on alcian blue with hyaluronidase treatment, whereas it will be preserved in mucinous carcinoma. This feature may be used in the distinction of the two entities. Metaplastic carcinoma may also be included in the differential diagnosis due to the presence of osseus and cartilaginous differentiation in the stroma. This too may present as a distinct mass with calcifications. This was not considered. Fibroepithelial neoplasms of the breast, fibroadenoma and phyllodes tumor, are both included in the differential diagnosis due to the myxofibromatous stroma. The epithelial component in both usually forms large sheets, which are accompanied by stripped myoepithelal nuclei. The key distinguishing features between fibroadenoma and phyllodes tumor are the cellularity of the stroma and the atypia of the stromal cells. Neither of these was considered due to the absence of stripped myoepithelial cell nuclei and myoepithelial cells in the ductal groups. Papillomas may be associated with chondroid metaplasia of its stroma, thus bringing this entity into the differential diagnosis. The epithelium of the papilloma will be arranged in papillary fronds and be associated with myoepithelial cells. Apocrine metaplasia may also be a feature of papillomas. Other salivary gland neoplasms showing myoepithelial differentiation may also come into the differential, particularly adenoid cystic carcinoma. Like pleomorphic adenoma, it typically also presents in the periareolar region. The key to distinguishing pleomorphic adenoma from adenoid cystic carcinoma is the appearance of the stroma on fine needle aspiration: in pleomorphic adenoma it is metachromatic and myxofibrillary, whereas in adenoid cystic carcinoma it forms hyaline globules. Usually, the distinction is readily made, except in pleomorphic adenomas with a significant canalicular pattern, which will produce clumps of epithelial cells with balls of stroma, mimicking adenoid cystic carcinoma. If the aspirate samples only this area, then the diagnosis may be missed.

Review of the Literature/Treatment Options:
The breast is a modified sweat gland and therefore may give rise to neoplasms more typically seen in the salivary glands, such as pleomorphic adenoma, adenoid cystic carcinoma, adenomyoepithelioma, and mucoepidermoid carcinoma. These neoplasms are rare in the breast, and therefore may cause difficulties in preoperative diagnosis. Pleomorphic adenomas of the breast occur predominantly in females, although they have rarely been reported in males. Most cases occur in the periareolar region. They are occasionally associated with nipple or skin retraction. They appear as well-defined masses on mammogram, but may have ill-defined borders. Calcifications are a frequent association. They usually present as small nodules of a few centimeters in size, but one measuring 17 cm, which developed over 30 years, has been recorded. Patients more typically present with solitary nodules, but may less frequently present with two or more nodules. As illustrated by our case, the clinical and mammographic findings may mimic malignancy. Preoperative diagnosis is difficult, due to misinterpretation of cytological and even frozen section samples as malignant. These misdiagnoses have resulted in overtreatment. Pleomorphic adenoma of the breast is a benign mammary neoplasm: no reports of metastasizing pleomorphic adenoma of the breast have been reported in the English literature, but they may recur locally. Excision with a rim of nonneoplastic tissue (2-5 mm), with follow-up for five years due to the risk of local recurrence, is the recommended treatment. Enucleation is not recommended, as this may be associated with recurrence. Sentinel lymph node biopsy, mastectomy and adjuvant therapy are not indicated. Pleomorphic adenoma of the breast arises from a single cell type that is capable of undergoing divergent differentiation, as does the salivary gland primary. The observation that many of these originate in the periareolar region suggests an origin from the large ducts. Intraductal growth and an association with intraductal papillomas have been observed. Chromosomal translocations frequently seen in salivary gland pleomorphic adenoma include rearrangements in the long arms of chromosomes 8(8q12), 12(12q15) and 6(6p21). Pleomorphic adenoma gene 1 (PLAG1) is activated by translocation in 8q12. The high mobility protein genes (HMG), are located on the other two loci. Pleomorphic adenomas of the breast have not yet been evaluated for these translocations. In the future, evaluation of samples for specific translocations may aid in the diagnosis of equivocal cases.

Conclusion(s):
Pleomorphic adenoma of the breast is a benign mammary gland neoplasm. Its clinical and imaging features may mimic malignancy. Pleomorphic adenoma is in the differential diagnosis of breast neoplasms with myxoid or chondroid appearing stroma. This entity should be considered as a possibility when evaluating aspiration samples from slowly growing neoplasms in the periareaolar region.

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