Definition
Carcinoma ex pleomorphic adenoma is defined as an epithelial and/or myoepithelial malignancy arising from a primary or recurrent pleomorphic adenoma. [1] It was first described by Beahrs et al in 1957. [2] In most instances the luminal epithelial cells undergo malignant change, though a combination of epithelial and myoepithelial malignancy or purely myoepithelial carcinoma may also occur.
Carcinoma ex pleomorphic adenoma represents the most common malignant change to occur in pleomorphic adenomas. Other malignant neoplasms to arise in the setting of a pleomorphic adenoma include carcinosarcoma (true malignant mixed tumor) and metastasizing pleomorphic adenoma.
Etiology
The exact etiologic factors associated with malignant transformation have been largely ill-defined; however, exposure to radiation is thought to be a factor (as it is with pleomorphic adenomas). Undoubtedly, carcinogenesis can also be attributed to the development and accumulation of genetic instabilities over time. [3, 4]
Epidemiology
Carcinoma ex pleomorphic adenoma develops in approximately 6% of pleomorphic adenomas; it constitutes 3.6% of all salivary gland tumors and 12% of malignant salivary gland tumors. [1, 5, 6, 7, 8]
This malignancy is most often seen in patients in the sixth to seventh decades of life with a median age at onset 10 to 20 years older than that for pleomorphic adenomas; this difference in age of peak incidence supports the supposition that longstanding tumors are more prone to malignant change (and justifies their removal). [9] Not surprisingly, carcinoma ex pleomorphic adenoma is rarely encountered in children or in patients younger than 30 years. [10, 11]
Some geographic prevalence variations have also been reported, though the significance of these findings is unknown. [4, 12, 13, 14]
Location
Carcinoma ex pleomorphic adenoma most commonly arises in the major salivary glands and more specifically the parotid gland (67%); the submandibular gland (15%) and sublingual gland (1%) are less often involved. [5, 6]
The tumor tends to occur in the deep lobe of the parotid, which may partly explain the low preoperative diagnostic accuracy and sensitivity of fine-needle aspiration. [14]
In the minor salivary glands, the palate is the most common site of occurrence. [7, 15, 16, 17, 18, 19]
Clinical Features and Imaging
Patients with carcinoma ex pleomorphic adenoma classically present with recent and rapid enlargement of a previously longstanding and slow-growing mass. [20, 21] Often, this enlargement is accompanied by other signs and symptoms suggestive of malignancy (eg, fixation to surrounding structures, [9] pain, skin infiltration, trismus, [14] facial nerve weakness, or palsy). [22, 23, 24, 25] In advanced cases, skin involvement and lymphadenopathy due to metastatic tumor may be seen. [26] The average period before malignant transformation is 20 years; about half of patients are aware of a swelling for about 2-3 years. [5]
In some patients there may be a history of previous surgeries for pleomorphic adenoma and/or recurrences; this history should raise the index of suspicion for malignant transformation and encourage careful examination of the resected tumor. [20, 27]
Gross Findings
The gross appearance of carcinoma ex pleomorphic adenoma varies, though the majority (approximately 64%) are infiltrative with poorly defined tumor margins. [1, 5] Residual pleomorphic adenoma is appreciable in most cases, often in the form of a well-circumscribed or sclerotic nodule. Foci of hemorrhage and necrosis may be seen. Malignancy may be not be apparent on gross examination, especially in cases of noninvasive or minimally invasive carcinoma. [20, 28]
Microscopic Findings
Carcinoma ex pleomorphic adenoma is not a specific diagnosis, as it only indicates a malignant carcinoma arising from an antecedent pleomorphic adenoma. The carcinoma tumor type must be specified and, if applicable, graded.
The most common tumor type seen in carcinoma ex pleomorphic adenoma is salivary duct carcinoma. High-grade adenocarcinoma (not otherwise specified), myoepithelial carcinoma, and epithelial-myoepithelial carcinomas are other common tumor types arising in this setting. Virtually all other malignant salivary gland tumors have been described, [1, 5, 9, 20, 22, 29, 30, 31] though some notion exists that this diversity may narrow as the molecular landscape of salivary gland tumors gets further refined. [32] The percentage of malignant component in carcinoma ex pleomorphic adenoma varies widely; in some instances, residual features of the tumor are difficult to appreciate. [33] Conversely, in other cases (notoriously, myoepithelial carcinoma), the atypia may be limited, and it may be difficult to discern the presence of malignancy. [27] See the images below.
Pathology of Carcinoma Ex Pleomorphic Adenoma. Undifferentiated carcinoma ex pleomorphic adenoma. Image A: In the right upper side of the photomicrograph, an undifferentiated carcinoma is seen adjacent to a benign pleomorphic adenoma component, which appears on the left side of the photomicrograph. Image B: At higher magnification, the undifferentiated carcinoma shows pleomorphic tumor cells with readily identifiable mitoses.
Pathology of Carcinoma Ex Pleomorphic Adenoma. Salivary duct carcinoma ex pleomorphic adenoma. Image A: The malignant portion of the tumor is shown with the characteristic comedo-type necrosis. Image B: The right side of the image shows a benign pleomorphic adenoma. Note the lymph-vascular invasion (arrows) from malignant component seen in Image A.
Pathology of Carcinoma Ex Pleomorphic Adenoma. Adenoid cystic carcinoma ex pleomorphic adenoma. Image A: Adenoid cystic carcinoma arising from a pleomorphic adenoma with prominent chondroid stroma (asterisk sign). Image B: At higher magnification, the characteristic cribriform pattern of adenoid cystic carcinoma with intervening hyalinized basal lamina is apparent.
Pathology of Carcinoma Ex Pleomorphic Adenoma. Myoepithelial carcinoma ex pleomorphic adenoma. Image A: The tumor is infiltrating the myxoid stroma of pleomorphic adenoma and almost completely replaces the substance of the benign tumor. Note the bland nature of the tumor cells in this malignancy; this may cause difficulties in recognizing malignancy in small biopsy specimens, as myoepithelial cells are a normal constituent of pleomorphic adenomas. Image B: The malignant nature of the tumor is obvious in this image. Note how the tumor extends into the surrounding tissue as infiltrative cords and single cells.
Carcinoma ex pleomorphic adenoma is categorized based on extent of invasion, as follows: intracapsular, minimally invasive, or widely invasive. [1, 20, 34, 35] Previously a cut-off of 1.5 mm (as measured from the pleomorphic adenoma capsule) was used to define minimally versus widely invasive tumors. More recently, the World Health Organization (WHO) does not specify a definitional cut-off, and favorable prognoses have even been reported with cut-offs of 4 mm to 6 mm. [1, 36, 37] At this time, best practice seems to dictate providing a measurement of tumor invasion beyond the pleomorphic adenoma capsule (when feasible), and reserving the minimally invasive category for carcinomas arising from a single nodule (as opposed to multiple nodules in a recurrent pleomorphic adenoma), for which the tumor breach of the capsule can be fully evaluated microscopically. [38] Not surprisingly, prognosis has been linked to the degree of invasion.
The histologic grading of carcinoma ex pleomorphic adenoma should follow the normal grading schemes of the particular carcinoma type. For example, a mucoepidermoid carcinoma ex pleomorphic adenoma should be graded as low, intermediate, or high grade, as is done for mucoepidermoid carcinomas occurring as individual tumors. Perineural invasion [20] and lymph-vascular invasion are commonly encountered in more invasive tumors; necrosis is often prominent in high-grade tumor types.
Immunohistochemistry
Similar to pleomorphic adenoma, immunohistochemical (IHC) studies mainly serve as an adjunct to histologic diagnosis for carcinoma ex pleomorphic adenomas. IHC studies may aid in highlighting epithelial and myoepithelial cell populations within the tumor. IHC studies for PLAG1 and HMGA2 protein may be helpful in confirming a prior pleomorphic adenoma in tumors where the malignant component has obliterated discernable pleomorphic adenoma features. It is worth remembering, however, that IHC for PLAG1 is sensitive but not specific for pleomorphic adenomas, and IHC for HMGA2 is specific but not sensitive.
Otherwise, IHC studies for p53 may occasionally be useful in the diagnosis, as p53 is often overexpressed in carcinoma ex pleomorphic adenoma and may be an early indicator of malignant change. [34, 39, 40, 41, 42] Similarly, an increased Ki-67 (MIB-1) is more common in the carcinoma component. Androgen receptor (AR) is expressed in salivary duct carcinoma, and may help highlight areas of carcinoma; however, AR can occasionally be positive in areas of apocrine differentiation in benign pleomorphic adenomas.
Immunoreactivity (overexpression) of HER2/neu (c-erbB-2) has also been associated with carcinoma and higher tumor grades. [4, 42, 43, 44, 45] A myriad of other possible (albeit perhaps less practical) indices of malignancy have been explored, including increased expression of cyclin A, [46] cyclin E, [47] and X-linked inhibitor of apoptosis protein (XIAP). [48]
Molecular/Genetics
PLAG1 and HMGA2 rearrangements are present in approximately 50-60% and 20-30% of pleomorphic adenomas and carcinoma ex pleomorphic adenomas, respectively. Again, these rearrangements may be helpful in confirming malignant transformation of tumor (versus de novo development), but they do not distinguish benign from malignant tumors.
Carcinoma ex pleomorphic adenomas are thought to develop via a multistep process of carcinogenesis involving progressive loss of heterozygosity (LOH) at chromosomes 8q, 12q, and then 17p. [4, 49, 50, 51] El-Naggar et al put forth that LOH on chromosome arms 8q and/or 12q are earlier events in a pleomorphic adenoma, and that LOH at 17p may portend progression to malignancy [51] ; in short, these regions are thought to contain tumor suppressor genes involved in the development of pleomorphic adenomas and carcinoma ex pleomorphic adenomas.
Early events involve PLAG1 and MYC on chromosome 8; malignant progression has been attributed to amplification of HMGIC, HMGA2, and MDM2 genes on chromosome 12. [4, 49, 50, 52]
Alterations in p53, a tumor suppressor gene located on chromosome 17p13, are commonly implicated in the pathogenesis of carcinoma ex pleomorphic adenoma. [4, 42, 53] Progression to carcinoma independent of p53, however, is also well documented. [54]
HER2/neu (c-erbB-2) overexpression has been found in a wide range (21-82%) of carcinoma ex pleomorphic adenoma cases, [4, 42, 45] and it may play a role in progression and malignant transformation of pleomorphic adenomas. This finding may have therapeutic relevance for some patients. [55]
Deregulation of cell cycle control proteins (eg, p16, cyclin D1, p21) has also been linked to malignant evolution of tumors. [4, 56, 57] Additionally, increased expression of numerous other genes and growth factors may play a role in angiogenesis, invasion, and progression of carcinoma ex pleomorphic adenoma. Some of these include COX-2, [58] fibroblast growth factor (FGF-2), transforming growth factor beta 1, transforming growth factor alpha, HGF-A (scatter factor), c-Met, and epidermal growth factor receptor. [58, 59, 60] Finally, alterations in some cell adhesion molecules (eg, decreased e-cadherin, decreased neural cell adhesion molecule (N-CAM), and expression of beta-catenin) have been associated with development of malignancy. [4, 61, 62, 63]
Tumor Spread and Staging
The Eighth edition of the American Joint Committee on Cancer (AJCC) [64] staging system for malignant tumors of the major salivary glands is shown below. [38]
Table 1. Tumor/Node/Metastasis (TNM) Classification for Carcinomas of the Major Salivary Glands (Open Table in a new window)
pT |
Primary tumor |
The phrases in *asterisks* include clinical findings required for AJCC staging. This clinical information may not be available to the pathologist but, if known, should be incorporated into the pathologic staging.
† Extraparenchymal extension is clinical or macroscopic evidence of invasion of soft tissues. Microscopic evidence alone does not constitute extraparenchymal extension for classification purposes. |
|
pT not assigned |
(Cannot be determined based on the available pathological information) |
| pT0 | No evidence of primary tumor |
pTis |
Carcinoma *in situ* |
pT1 |
Tumor 2 cm or smaller in the greatest dimension *without extraparenchymal extension*† |
pT2 |
Tumor larger than 2 cm but not larger than 4 cm in the greatest dimension *without extraparenchymal extension*† |
pT3 |
Tumor larger than 4 cm and/or tumor *having extraparenchymal extension*† |
pT4a |
Moderately advanced local disease. Tumor invades skin, mandible, ear canal, and/or facial nerve. |
pT4b |
Very advanced local disease. Tumor invades skull base, and/or pterygoid plates and/or encases the carotid artery. |
| pT4 | (Subcategory cannot be determined) |
pN |
Regional lymph nodes |
Midline nodes are considered ipsilateral nodes.
Pathological extranodal extension (ENE) should be recorded as ENE(−) or ENE(+). Measurement of the metastatic focus in the lymph nodes is based on the largest metastatic deposit size, which may include matted or fused lymph nodes. |
|
pN not assigned |
(No nodes submitted or found) |
| pN not assigned | (Cannot be determined based on the available pathological information) |
| pN0 | No regional lymph node metastasis |
| pN1 | Metastasis in a single ipsilateral lymph node, 3 cm or smaller in the greatest dimension and ENE(-) |
pN2a |
Metastasis in a single ipsilateral node 3 cm or smaller in the greatest dimension and ENE(+); or a single ipsilateral node larger than 3 cm but not larger than 6 cm in the greatest dimension and ENE(-) |
pN2b |
Metastases in multiple ipsilateral nodes, none larger than 6 cm in the greatest dimension and ENE(-) |
pN2c |
Metastases in bilateral or contralateral lymph node(s), none larger than 6 cm in the greatest dimension and ENE(-) |
| pN2 | (Subcategory cannot be determined) |
pN3a |
Metastasis in a lymph node larger than 6 cm in the greatest dimension and ENE(-) |
| pN3b | Metastasis in a single ipsilateral node larger than 3 cm in the greatest dimension and ENE(+); or multiple ipsilateral, contralateral, or bilateral nodes any with ENE(+); or a single contralateral node of any size and ENE(+) |
| pN3 | (Subcategory cannot be determined) |
pM |
Distant metastasis (required only if confirmed pathologically) |
Not applicable |
pM cannot be determined from the submitted specimen(s) |
pM1 |
Distant metastasis |
Table 2. AJCC Prognostic Stage Groups [64] (Open Table in a new window)
T |
M |
N | Stage Group |
Tis |
N0 |
M0 | 0 |
T1 |
N0 |
M0 | I |
T2 |
N0 |
M0 | II |
T3 |
N0 |
M0 | III |
T0, T1, T2, T3 |
N1 |
M0 | III |
T4a |
N0, N1 |
M0 | IVA |
T0, T1, T2, T3, T4a |
N2 |
M0 | IVA |
Any T |
N3 |
M0 | IVB |
T4b |
Any N |
M0 | IVB |
Any T |
Any N |
M1 | IVC |
AJCC = American Joint Committee on Cancer. |
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Tumor reporting for carcinoma ex pleomorphic adenoma should include the following:
-
Tumor stage including size and lymph node status (see the above table)
-
Carcinoma tumor type
-
Carcinoma tumor grade (if applicable)
-
Extent of invasion (carcinoma in situ, intracapsular, minimally invasive, widely invasive) with measurement of the tumor distance beyond the capsule when feasible
-
Lymph-vascular invasion, perineural invasion, margin status
For carcinoma ex pleomorphic adenoma arising in the minor salivary glands, staging is determined in accordance with the reporting system for the region of occurrence.
Prognosis and Predictive Factors
Carcinoma ex pleomorphic adenoma encompasses a diverse groups of neoplasms given the potential spectrum of carcinoma subtypes, tumor grades, and extent of invasion. On the whole, carcinoma ex pleomorphic adenoma is regarded as an aggressive malignancy with a 5-year survival of 25-65%; the majority (~70%) of patients succumb to local or distant metastases. [1]
Extent of invasion appears to be the most useful metric to risk stratify this diverse group of tumors (perhaps even more significant than pT classification), and the most meaningful threshold is still being established. Patients with intracapsular and minimally invasive tumors (< 4-6 mm in this case) have more favorable outcomes. [1, 36, 65] More widely invasive tumors behave aggressively and convey an increased risk of recurrence, metastasis, and fatality. [5, 20, 26] Common metastatic sites include lymph nodes, bone (especially vertebral bodies), and brain.
As would be expected, tumor type, grade, and stage of the disease also play an important role in prognosis.
-
Pathology of Carcinoma Ex Pleomorphic Adenoma. Undifferentiated carcinoma ex pleomorphic adenoma. Image A: In the right upper side of the photomicrograph, an undifferentiated carcinoma is seen adjacent to a benign pleomorphic adenoma component, which appears on the left side of the photomicrograph. Image B: At higher magnification, the undifferentiated carcinoma shows pleomorphic tumor cells with readily identifiable mitoses.
-
Pathology of Carcinoma Ex Pleomorphic Adenoma. Salivary duct carcinoma ex pleomorphic adenoma. Image A: The malignant portion of the tumor is shown with the characteristic comedo-type necrosis. Image B: The right side of the image shows a benign pleomorphic adenoma. Note the lymph-vascular invasion (arrows) from malignant component seen in Image A.
-
Pathology of Carcinoma Ex Pleomorphic Adenoma. Adenoid cystic carcinoma ex pleomorphic adenoma. Image A: Adenoid cystic carcinoma arising from a pleomorphic adenoma with prominent chondroid stroma (asterisk sign). Image B: At higher magnification, the characteristic cribriform pattern of adenoid cystic carcinoma with intervening hyalinized basal lamina is apparent.
-
Pathology of Carcinoma Ex Pleomorphic Adenoma. Myoepithelial carcinoma ex pleomorphic adenoma. Image A: The tumor is infiltrating the myxoid stroma of pleomorphic adenoma and almost completely replaces the substance of the benign tumor. Note the bland nature of the tumor cells in this malignancy; this may cause difficulties in recognizing malignancy in small biopsy specimens, as myoepithelial cells are a normal constituent of pleomorphic adenomas. Image B: The malignant nature of the tumor is obvious in this image. Note how the tumor extends into the surrounding tissue as infiltrative cords and single cells.
Tables
pT |
Primary tumor |
The phrases in *asterisks* include clinical findings required for AJCC staging. This clinical information may not be available to the pathologist but, if known, should be incorporated into the pathologic staging.
† Extraparenchymal extension is clinical or macroscopic evidence of invasion of soft tissues. Microscopic evidence alone does not constitute extraparenchymal extension for classification purposes. |
|
pT not assigned |
(Cannot be determined based on the available pathological information) |
| pT0 | No evidence of primary tumor |
pTis |
Carcinoma *in situ* |
pT1 |
Tumor 2 cm or smaller in the greatest dimension *without extraparenchymal extension*† |
pT2 |
Tumor larger than 2 cm but not larger than 4 cm in the greatest dimension *without extraparenchymal extension*† |
pT3 |
Tumor larger than 4 cm and/or tumor *having extraparenchymal extension*† |
pT4a |
Moderately advanced local disease. Tumor invades skin, mandible, ear canal, and/or facial nerve. |
pT4b |
Very advanced local disease. Tumor invades skull base, and/or pterygoid plates and/or encases the carotid artery. |
| pT4 | (Subcategory cannot be determined) |
pN |
Regional lymph nodes |
Midline nodes are considered ipsilateral nodes.
Pathological extranodal extension (ENE) should be recorded as ENE(−) or ENE(+). Measurement of the metastatic focus in the lymph nodes is based on the largest metastatic deposit size, which may include matted or fused lymph nodes. |
|
pN not assigned |
(No nodes submitted or found) |
| pN not assigned | (Cannot be determined based on the available pathological information) |
| pN0 | No regional lymph node metastasis |
| pN1 | Metastasis in a single ipsilateral lymph node, 3 cm or smaller in the greatest dimension and ENE(-) |
pN2a |
Metastasis in a single ipsilateral node 3 cm or smaller in the greatest dimension and ENE(+); or a single ipsilateral node larger than 3 cm but not larger than 6 cm in the greatest dimension and ENE(-) |
pN2b |
Metastases in multiple ipsilateral nodes, none larger than 6 cm in the greatest dimension and ENE(-) |
pN2c |
Metastases in bilateral or contralateral lymph node(s), none larger than 6 cm in the greatest dimension and ENE(-) |
| pN2 | (Subcategory cannot be determined) |
pN3a |
Metastasis in a lymph node larger than 6 cm in the greatest dimension and ENE(-) |
| pN3b | Metastasis in a single ipsilateral node larger than 3 cm in the greatest dimension and ENE(+); or multiple ipsilateral, contralateral, or bilateral nodes any with ENE(+); or a single contralateral node of any size and ENE(+) |
| pN3 | (Subcategory cannot be determined) |
pM |
Distant metastasis (required only if confirmed pathologically) |
Not applicable |
pM cannot be determined from the submitted specimen(s) |
pM1 |
Distant metastasis |
T |
M |
N | Stage Group |
Tis |
N0 |
M0 | 0 |
T1 |
N0 |
M0 | I |
T2 |
N0 |
M0 | II |
T3 |
N0 |
M0 | III |
T0, T1, T2, T3 |
N1 |
M0 | III |
T4a |
N0, N1 |
M0 | IVA |
T0, T1, T2, T3, T4a |
N2 |
M0 | IVA |
Any T |
N3 |
M0 | IVB |
T4b |
Any N |
M0 | IVB |
Any T |
Any N |
M1 | IVC |
AJCC = American Joint Committee on Cancer. |
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