Pleomorphic Adenoma (Mixed Tumor)
Key Points
Pleomorphic adenomas arise most often in the lacrimal or salivary glands, and less commonly from ectopic periorbital lacrimal gland tissue, sweat glands of Moll, or accessory lacrimal glands of Krause and Wolfring in the eyelids
They are characterized by translocations or intrachromosomal rearrangements with breakpoints affecting 8q12 in 50% and 12q14-15 in 10% to 15%
Lesions are very slow-growing, small, smooth, firm, nontender, nodular masses that may be associated with madarosis and telangiectasias
Treatment is with complete local surgical resection and eyelid reconstruction when necessary
The prognosis is excellent, and the reported eyelid cases showed no recurrence or malignant transformation
Mixed tumor of the skin was first described by Billroth in 1859,1 and since then the terms “chondroid syringoma,” “benign mixed tumor,” and “pleomorphic adenoma” all have been used interchangeably for this lesion. In recent years the term “pleomorphic adenoma” has been preferred for salivary gland neoplasms,2 while mixed tumor is preferred for skin tumors.2 Pleomorphic adenoma (PA) most often arises in the lacrimal or salivary glands.3,4,5 Less commonly it may arise from ectopic periorbital lacrimal gland tissue, sweat glands of Moll, or accessory lacrimal glands of Krause and Wolfring in the eyelids.6,7,8,9,10,11,12,13,14
At birth, there are between 20 and 40 accessory lacrimal glands of Krause in the upper conjunctival fornix and 6 to 8 laterally in the lower fornix.15,16,17 Three to four accessory lacrimal glands of Wolfring are larger and are situated at the superior border of the tarsus in the upper eyelid.15 Accessory lacrimal glands may also be encountered in the caruncle and in the plica semilunaris18,19,20 Although ectopic lacrimal gland tissue has frequently been reported in the orbit, eye, and eyelid,21,22,23,24,25,26,27,28 pleomorphic adenoma arising from ectopic lacrimal glands is rare,29,30 and even less frequent is adenoid cystic carcinoma.13,20
Cutaneous malignant PA, usually termed “malignant chondroid syringoma”31 or “malignant mixed tumor,” is very rare and usually develops on the torso or extremities, but about 25% may be located on the face and scalp.32,33 It presents most frequently as a nonulcerated, slow-growing subcutaneous or intradermal nodule.34,35,36,37,38,39,40 In contrast to benign cutaneous PA, malignant lesions tend to occur more frequently in women, with no age preference. They can develop de novo or less commonly from incompletely resected benign PA lesions. Malignant transformation has not been reported in pleomorphic adenomas arising in the eyelid. Nevertheless, because PA of the lacrimal and salivary glands carries a small but significant risk of malignant transformation if not completely excised, it is likely that this may also be seen eventually in tumors arising in ectopic or accessory lacrimal glands.
Etiology and Pathogenesis
Benign pleomorphic adenomas of the salivary glands are characterized by translocations or intrachromosomal rearrangements with breakpoints affecting 8q12 (in 50%) and 12q14-15 (in 10%-15%).41,42 The translocations and rearrangements result in gene fusions involving the transcription factor genes PLAG1 and HMGA2.41,42,43,44 A subset of cutaneous mixed tumors feature PLAG1 rearrangement with aberrant nuclear expression of PLAG1 protein,45 while other tumors have EWSR1 rearrangement.46 Another study showed PLAG1 expression by epithelial cells of cutaneous mixed tumors in the absence of fusion gene transcripts detectable using a reverse transcriptase-polymerase chain reaction method.47 Oncogenic activation of the PLAG1 gene on 8q12 is a crucial event in the formation of pleomorphic adenomas of the salivary glands48 and some cutaneous mixed tumors.47 Activation mainly results from recurrent chromosomal translocations that lead to promoter substitution between PLAG1 and several other genes,43,49 leading to an exchange of the regulatory control elements.48 The replacement of the PLAG1 promoter, inactive in adult salivary glands, by a strong promoter derived from the translocation partner, leads to ectopic expression of PLAG1 in the tumor cells and presumably results in deregulation of PLAG1 target genes, causing salivary gland tumorigenesis.50
Clinical Characteristics
Fewer than 50 cases of pleomorphic adenoma arising in the eyelids have been reported. Most patients at presentation are 50 to 60 years old, with a range of 12 to 84 years, and there is a strong male predilection. The right and left sides are equally affected, and the lower eyelid is involved in 55% of the reported cases. Most lesions are very slow growing over 1 to 20 years before presentation. The vast majority of tumors
are small, with 96% being equal to or less than 1 cm in diameter. Clinical examination typically show a smooth, firm, nontender, nodular mass in 88% of cases (Figures 103.1 and 103.2), with rare lesions being ulcerative or cystic. Madarosis and surface telangiectasias is seen in about 25% of cases. The caruncle can be involved in 6% of affected patients.9,10,12,18,31,51,52,53,54,55,56,57,58,59,60,61
are small, with 96% being equal to or less than 1 cm in diameter. Clinical examination typically show a smooth, firm, nontender, nodular mass in 88% of cases (Figures 103.1 and 103.2), with rare lesions being ulcerative or cystic. Madarosis and surface telangiectasias is seen in about 25% of cases. The caruncle can be involved in 6% of affected patients.9,10,12,18,31,51,52,53,54,55,56,57,58,59,60,61
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