Pathology of Metastasizing Pleomorphic Adenoma

There are three main patterns of malignant change that occur in pleomorphic adenoma: metastasizing pleomorphic adenoma (MPA), carcinoma ex pleomorphic adenoma, and true malignant mixed tumor (carcinosarcoma). Metastasizing pleomorphic adenoma (the term currently preferred by the World Health Organization [WHO]) is also known as metastasizing benign pleomorphic adenoma, metastasizing benign mixed tumor, and metastasizing mixed tumor.

By definition, metastasizing pleomorphic adenoma is characterized by the presence of one or more foci of metastatic, histologically benign pleomorphic adenoma. The stage of the tumor is variable, depending on the site of metastasis and the extent of the metastatic foci. Typically, pleomorphic adenoma of major or minor salivary gland origin is present at the time of diagnosis, or the patient has a history of such adenoma, which may be recurrent.

It is worthwhile to note that the 2015 WHO classification of head and neck tumors considers metatsasizing pleomorphic adenoma as a malignant tumor of epithelial origin. It is also important to point out that the International Classifications of Diseases for Oncology (ICD-O) assigns a benign behavioral code "/1" that corresponds to neoplasia of uncertain and unknown behavior.

In a 2003 review by Nouraei et al, 42 cases of metastasizing pleomorphic adenoma were reported in the English-language literature between 1953 and 2005. ^[1] An exhaustive literature review by Marioni et al, also in 2003, identified approximately 60 recorded cases since 1942. ^[2]  Knight et al, in a 2015 systematic review of the literature, found 80 known cases from 1942 to 2014. ^[3]

It should be noted, however, that the exact number of cases of metastasizing pleomorphic adenoma has been a matter of controversy among reviewing authors. Some investigators have questioned the very existence of this entity or the accuracy of the diagnostic criteria used in many of the reported cases, ^{[4, 5]} whereas others have reaffirmed the existence of this disease. ^[6]

In the reported cases, the distribution of metastasizing pleomorphic adenoma among males and females was almost statistically equal. Patients ranged in age from 8 to 73 years (average, 32.9 ± 18.5 years). ^[1] The time from initial presentation to the detection of metastases for patients who had no intervening local recurrences was 12.3 ± 8.6 years. ^[1] For patients with a history of local recurrence, it was 16.9 ± 13.3 years. ^[1] Intervals of up to 55 years have been recorded. ^{[1, 5, 6, 7]} The parotid gland is the most common primary site. ^[1]

The etiology of metastasizing pleomorphic adenoma is not clearly understood, but a number of theories have been put forward. ^{[2, 5, 6]} In most reported cases, a history of multiple local recurrences of pleomorphic adenoma is seen, although in some cases, such a history is absent. ^{[8, 9, 10, 11]} Khademi et al reported the simultaneous detection of a primary benign pleomorphic adenoma of the minor salivary glands of the tongue and a concurrent benign metastasizing pleomorphic adenoma in the cervical lymph nodes. ^[12]  Watson et al reported a fatal case of metastasizing pleomorphic salivary adenoma, in which a 61 year-old woman had a massive untreated minor salivary gland pleopmorphic adenoma (in the palatal vault) and concurrent ipsilateral cervical node metastases. ^[13]

Metastasis may occur via the hematogenous or lymphatic route. It has been postulated that the tumor may gain access to the vascular or lymphatic system as a result of iatrogenic manipulation during a surgical procedure, increasing the risk of involvement of the angiolymphatic system, as well as the risk of multiple recurrences. In a series of 24 tumors reported by Chen and Tu, 20 lesions spread via the hematogenous route, whereas 4 spread through the lymphatic channels. ^[5] Wenig et al reported spread through both routes as well. ^[6]

Wermuth et al suggested that pulmonary metastasis of pleomorphic adenoma could arise from aspiration of tumor cells shed from salivary glands into the pharynx. ^[14]

Some investigators hypothesize that there is an intermediate link in the transformation of pleomorphic adenoma into carcinoma ex pleomorphic adenoma. ^[15]

In a review by Nouraei et al, the parotid gland was by far the most common primary site (74%) of metastasizing pleomorphic adenoma, followed by the minor salivary glands (17%) and the submandibular gland (10%). ^[1]

A case report by Alshagroud et al detailed the incidental finding of a metastasizing pleomorphic adenoma affecting the mandible of a 17-year-old female who was undergoing preoperative evaluation for extraction of her third molars. ^[16] The lesion was preceded by a submandibular gland pleomorphic adenoma.

Metastasis occurs primarily to bone (45%), followed by the head and neck (43%) and the lungs (36%). ^{[1, 2, 17]} Other sites of metastasis include the skin, the liver, ^[18] the retroperitoneum, the kidney, ^{[19, 20]} lymph nodes, and the central nervous system.

In a 2015 systematic review conducted by Knight et al, similar findings were reported, with metastastatic distribution as follows: bone (36.6%), lung (33.8%), and cervical lymph nodes (20.1%). ^[3]

In 2018, Koyama et al reported simultaneous multiple organ metastases to the bone, lung, bilateral kidneys, liver, and perineum in a 68 year-old-female with recurrent pleomorphic adenoma of the right parotid gland that was originally operated on at age 40 years, with a tumor recurrence occuring at age of 53 years that was also resected. ^[21]

Most patients (60%) with metastasizing pleomorphic adenoma present with symptoms and signs related to the area of the metastasis. However, some lesions may be asymptomatic; such lesions are sometimes discovered incidentally during a workup. Metastasis may be solitary, or multiple metastases may be present.

Among symptomatic patients, a head and neck mass, lower back pain, abdominal mass, cranial nerve palsies, nasal obstruction, acute sopinal cord compression, pathologic fractures, and hip pain were among the various symptoms reported.

The clinical history is essential for differentiating metastasizing pleomorphic adenoma from a primary pleomorphic adenoma that is arising in an unusual site.

In cases of recurrent or longstanding pleomorphic adenomas, complementary radiologic studies to rule out metastasizing benign pleomophic adenoma are advised, such as a full body computed tomography (CT) scanning, magnetic resonance imaging (MRI) and/or positron-emission tomography (PET) scanning. ^[22]  Koyama et al also recommended full body F-18 fluorodeoxyglucose PET/CT body imaging in their case of a woman with simultaneous multiple organ metastases; they argued that their diligence in follow-up imaging was key in discovering the multiple site metastases. ^[21]

Gross findings

Both the primary tumor and the metastatic lesion of metastasizing pleomorphic adenoma appear well circumscribed.

Microscopic findings

The diagnosis of metastasizing pleomorphic adenoma should fulfill two criteria. ^{[7, 23]} First, the primary and metastasizing tumors must not show changes indicative of malignancy (ie, anaplasia, necrosis, increased mitosis, and an invasive growth pattern). Second, the primary site must be separate from the metastatic site, and both sites must show the features of biphasic benign pleomorphic adenoma. Although atypia may occasionally be seen, such atypia should be consonant with the atypia encountered in pleomorphic adenomas in general.

To date, there have been no reports of morphologic features in the original pleomorphic adenoma that can help predict the tumor's ability or inability to metastasize; histologic analyses of parameters such as cellularity, mitotic rate, or infiltrative growth pattern have not revealed any significant leads. ^[23]

Although primary and recurrent pleomorphic adenomas are usually of similar appearance, the histologic subtypes may not be identical with regard to the ratio of the epithelial/myoepithelial components to the stromal components. In some cases, metastatic deposits show a more cellular yet benign-appearing component than the original tumor (see the image below). ^[24]

Pathology of metastasizing pleomorphic adenoma. The image shows metastasizing pleomorphic adenoma of the skin on the lower anterior neck of a patient who had previously undergone resection of a right parotid pleomorphic adenoma. There was no recurrence at the primary site. The neck nodule manifested itself 3 years after resection (unreported case).

With regard to immunohistochemistry, there are no differences between the original tumor and the metastasizing pleomorphic adenoma. The immunoprofiles of the primary tumor and the metastasizing tumor are similar and delineate the epithelial, myoepithelial, and modified myoepithelial cells encountered in pleomorphic adenoma. ^[25]

In an analysis of three skeletal metastases from a pleomorphic adenoma, Jin et al found that the karyotypic features of the metastases were different from those of benign pleomorphic adenoma and carcinoma ex pleomorphic adenoma. ^[26] Their findings suggested that deletions of one or more tumor suppressor genes (3p deletions), which are frequently seen in a large variety of malignant epithelial neoplasms, might be important in the progression of some pleomorphic adenomas to metastasis.

In a single case study, Takeuchi et al did not find that the oncogenes and tumor suppressor genes they tested (bcl -2, c-erbB -2, c-myc, L-myc, N-myc, Ha-ras, Ki-ras, RB, p16, and p53) played a role—that is, they observed no rearrangement or overexpression. ^[27]  In addition, immunohistochemical studies did not document any aberrance in the expression of the tumor suppressor gene products RB, p16, and p53 within the tumor.

In an extensive flow-cytometric analysis of the tumors and their metastatic counterparts, Wenig et al failed to uncover any significant predictive findings. ^[6]

A 2015 study by Mariano et al took tumor DNA samples from primary (parotid) salivary gland tumors and secondary (scalp skin) metastasizing pleomorphic adenomas, subjected them to array comparative genomic hybridization, and analyzed the data with NEXUS COPY NUMBER DISCOVERY. ^[28] The investigators suggested their findings indicated a clonal origin of the secondary metastasizing pleomorphic adenomas, as both tumors shared a common profile of genomic copy number alterations. Moreover, the primary tumor had a specific pattern of copy number alterations that had the potential to explain the metastasizing characteristic, whereas the secondary metastasizing pleomorphic adenomas showed a more unbalanced genome. ^[28]

Although metastasizing pleomorphic adenoma appears histologically benign, its clinically observed behavior generally supports the premise that it should be regarded as a true malignant entity, mostly of low grade but sometimes aggressive. In reported cases, mortality ranged from 20% to 43%. ^{[6, 29, 30, 31]}

The World Health Organization reported that 40% of the patients die of the disease, 47% live free of the disease, and 13% live with the disease ^[32]  The 5-year disease-specific and disease-free survival were 58% and 50%, respectively. ^[33] There is no relation between tumor behavior and outcome with regard to the primary site of the tumor. ^[34]

Nouraei et al found that patients presenting with metastasis within 10 years of the occurrence of their initial primary tumor had a worse prognosis in comparison to those presenting with metastasis more than 10 years after the occurrence of their primary tumor. ^[1] These investigators also found that metastasis to multiple locations was an independent negative prognostic factor. ^[1]

Immunosuppression seems to contribute to the rapid progression of this benign-appearing tumor in a fashion similar to that encountered with many malignancies. ^[29]