A rare case of an aggressive polymorphous adenocarcinoma of minor salivary gland in the retro-maxilla

Abstract

Polymorphous adenocarcinoma (PAC) is a low-grade malignant tumour of minor salivary glands of the oral cavity, which rarely presents with invasive features. Low metastatic and excellent survival rates are some of its favorable features. A 36-year-old woman reported with swelling, pain, and mobility of teeth in the left upper inner cheek region. Contrast enhanced computed tomography (CECT) revealed a large, lobulated, heterogenous mass in the left retro-maxillary region with a few enlarged left cervical lymph nodes (levels IB and II). After surgery, the final histopathology report gave a definitive diagnosis of PAC with certain invasive characteristics – perineural invasion, infiltration into skeletal muscle, and depth of invasion of 10 mm, which recurred in a different location 1.5 years later. A few predictable features of PAC include incidence in elderly women, asymptomatic presentation, occurrence in the posterior hard of soft palate, very low incidence of nodal or distant metastases, perineural spread, skeletal muscle infiltration, and low rates of recurrence with good survival outcomes. However, in our case, the patient appeared to present with a relatively aggressive form of PAC, considering her young age, symptomatic presentation, uncommon anatomic location in the retro-maxilla, cervical nodal metastasis, perineural and skeletal muscle infiltration, and local recurrence within a short period. Although PAC is a low-grade tumour with excellent prognosis, it may occasionally present with invasive characteristics, and early diagnosis and prompt management with strict adherence to post-operative regimens and follow-up is of prime importance to prevent any untoward outcomes.

INTRODUCTION

Polymorphous adenocarcinoma (PAC) is a low-grade malignant tumour of salivary glands. The term was coined by Evans and Batsakis in 1984.[1] It most commonly arises from minor salivary glands, the palate being the most likely site. However, the involvement of major salivary glands is not rare.[2,3] Most frequently affected are women during their sixth and seventh decades of life. The clinical presentation can range from asymptomatic swellings to painful ulcerations, albeit occasional.[2,4] The tumour is characterised by cytologic uniformity and architectural diversity with varied histological patterns such as tubular, lobular, trabecular, cribriform, cystic, and papillary-cystic, which are formed by single-layer strands of cells.[5] Overall, it is a low-grade malignancy with an infiltrative growth pattern. Low metastatic and excellent survival rates are some of the favourable features.[2,3,4] However, careful and systematic follow-up is crucial since there are reports of recurrences even after several years of surgery.[2]

In this case report, we highlight a case of an aggressive PAC in a rare anatomic location, the retro-maxilla, which was followed by a recurrence in the buccal space and submandibular region.

CASE REPORT

A 36-year-old woman reported a swelling in her left inner cheek which was asymptomatic when it first appeared 6 years ago, but gradually increased in size and symptoms over the years. On examination, there was a well-defined dome-shaped swelling concerning the left buccal mucosa measuring approximately 2 × 2 × 1 cm. It was a firm and mobile swelling, associated with pain, discomfort, and multiple mobile teeth. There was no bleeding or induration associated.

Contrast-enhanced computed tomography (CECT) revealed a heterogeneously enhancing soft tissue density lesion in the left masticator space, indicative of a retromaxillary location [Figure 1]. It also showed a few enlarged left levels IB and II cervical lymph nodes. A minor salivary gland tumour, most likely mucoepidermoid carcinoma, was suspected. Based on the clinical diagnosis, definitive surgery was planned. She underwent wide local excision and reconstruction with a buccal fat pad along with ipsilateral supraomohyoid neck dissection. The specimen was sent for histopathological evaluation (HPE) [Figure 2].

Figure 1.

CECT image showing a heterogeneously enhancing soft tissue density lesion in the left retro-maxillary region

Figure 2.

Specimen image after wide local excision

On microscopy, the lesion showed stratified squamous epithelium overlying stroma containing circumscribed tumour with infiltrative margins composed of trabeculae, anastomosing cords and sheets of monomorphic malignant cells with oval to round nuclei, irregular nuclear contour, fine chromatin, moderate to scant cytoplasm, some with clear cytoplasm, foci of brisk mitosis (up to 15/10hpf in some areas) surrounded by fibrous to focally myxoid stroma [Figure 3a and b]. The final histopathology report was suggestive of PAC of minor salivary gland in relation to left retro-maxilla. Additionally, there was evidence of perineural invasion and skeletal muscle infiltration. All the margins were free of tumour; however, the depth of invasion was 10 mm. Immunohistochemistry (IHC) was positive for Cytokeratin7 [Figure 3c] and SOX10 [Figure 3d], and negative for p63, p40, smooth muscle antigen, S100 and epithelial membrane antigen. This confirmed the diagnosis and ruled out its morphologic mimics and metastasis.

Figure 3.

(a): Tumour with infiltrative margin composed of trabeculae, anastomosing cords and sheets, H&E X40; (b): Tumour with monomorphic malignant cells, H&E × 400; (c): Tumour cells positive for CK7, Cytokeratin7 ×100; (d): Tumour cells positive for SOX10, SOX10 and X100

Based on the report, the patient was advised post-operative adjuvant radiotherapy (RT). But she did not comply. She had been on regular follow-up, but after 1.5 years, she presented with an ovoid growth in the left buccal space. It was a solid, well-circumscribed swelling extending to the submandibular region measuring approximately 3 × 3 × 3 cm [Figure 4]. Fine needle aspiration cytology (FNAC) was suggestive of deposits of polymorphous adenocarcinoma, and thus confirmed recurrence. She underwent wide excision and reconstruction with a cervicofacial rotation flap [Figure 5]. She has been on follow-up for the past 6 months with no signs of complications or recurrence.

Figure 4.

CECT image showing lesion in the left buccal space extending to the submandibular region

Figure 5.

Intra-operative image of the tumour

DISCUSSION

According to the recent WHO classification, PAC includes cribriform adenocarcinoma of minor salivary glands (CAMSG) under the same subheading.[6] Terminologies like ‘lobular carcinoma’ and ‘terminal duct carcinoma’ have often been used interchangeably in the past.[7] The annual incidence is roughly 0.051 cases per 100,000 individuals and is the second most common minor salivary gland tumour of the oral cavity after mucoepidermoid carcinoma. Predominantly affecting women, it occurs above 40 years of age, with the mean age at diagnosis being 61.3 years.[8] In our case, although the patient was female, her age at presentation, 36 years, was much younger than usually documented in the literature.

The primary anatomic location affected by PAC is posterior hard and soft palate.[2,3,8,9] Buccal and labial mucosa are the next most frequently involved areas. The least frequently affected sites are the nasal cavity, paranasal sinuses, lacrimal apparatus, trachea, larynx, and breast. CAMSG, on the other hand, can occur in the base of tongue, upper lip, tonsils, retromolar region, and even the epiglottis.[8,9] However, the occurrence of PAC in the retro-maxilla, as was seen in our case, has not been regularly documented in literature.

PAC usually presents as a slow-growing, asymptomatic swelling. When detected late due to inconspicuous locations, patients may present with pain, ulceration, or bleeding. Adherence to underlying structures and bone erosion is rare, usually affecting the hard palate. Perivascular and perineural invasions have been reported occasionally.[4] The anatomic location and the lymphatic network of the area play a role in metastasis and the distant sites involved are usually the lungs, abdomen, orbit, or skin.[4,7,8,9,10] In our case, the patient initially presented with a swelling of significant duration, justifying the slow-growing nature of the tumour. However, the pain associated with the swelling indicates that when left unattended for a long time, PAC may become potentially symptomatic. Persistent pain, in turn, led to compromised oral hygiene maintenance, which consequently resulted in mobility of teeth due to periodontitis.

The pre-operative imaging modalities used are CT, magnetic resonance imaging (MRI), positron emission tomography CT (PET-CT). They help to determine the local extent, bone and muscle involvement, nodal and regional metastases and perineural invasion. Ultrasonography (USG) may not be useful in diagnosing the tumour, but it is a useful modality for guiding FNAC.[9] However, the gold standard for diagnosis remains incisional biopsy with a margin of normal tissue. Management protocol involves complete and wide surgical excision, which provides the best loco-regional control of PAC. Bony involvement, most commonly palate or maxilla, may necessitate alveolectomy or maxillectomy. Obturators can be used to restore function post-operatively. Other reconstruction modalities include non-vascularised and vascularised flaps.[9] Neck dissection remains controversial due to low incidence of nodal metastases; however, elective neck dissection is recommended for better long-term survival and prognosis. The role of post-operative adjuvant RT should be emphasised especially in case of positive margins, bone or muscle involvement, perineural spread, paranasal sinus locations or positive cervical metastases.[9,11]

Microscopically, PAC cells are uniform in shape – round to polygonal – with indistinct borders, abundant eosinophilic cytoplasm, and round to oval vesicular nuclei. Mitotic figures and nuclear atypia are uncommon. A remarkable mixture of various histological patterns is the landmark of PAC, including cords, tubules, islands, single-cell “Indian-file infiltration” and cribriform aggregates often mimicking a mucoid-myxoid matrix. The periphery of the tumour is characterised by single cell filing reminiscent such as that seen in lobular carcinoma of the breast and is a very valuable diagnostic feature. Two significant features of this neoplasm are morphological polymorphism and the common finding of cribriform or multicystic areas. Lesions that are chiefly papillary cystic are known to have a worse prognosis.[12] 73-89% of PAC harbor PRKD1 E710D hotspot mutation. 6-11% contain fusions involving PRKD1, PRKD2 or PRKD3 genes, with the fusion partners being ARID1A or DDX3X.[12,13] Although infiltration into surrounding adipose and connective tissue may be seen, skeletal muscle infiltration is rare. However, our patient showed signs of perineural invasion and skeletal muscle infiltration with a depth of invasion of 10 mm.

Due to the architectural pattern of PAC, the common differentials include pleomorphic adenoma (PA), adenoid cystic carcinoma (ACC), basal cell adenoma and secretory carcinoma.[2,3,8,9,10] Morphology and immunohistochemistry help in precise diagnosis. PA can be confirmed on morphology due to presence of triphasic ductal, myoepithelial and stromal components. Furthermore, PLAG1 and HMGA2 may be used as surrogate immunohistochemical markers for underlying PLAG1 or HMGA2 fusion. ACC is p63 and p40 positive while PAC is p40 negative. Secretory carcinoma is S100 positive like PAC, but in addition characteristically, mammaglobin positive.[12,13,14] In small biopsies, immunohistochemistry for CD117 (c-kit), GFAP and myoepithelial markers (e.g. calponin, aSMA, p63, SOX10) may be helpful if pleomorphic adenoma, polymorphous adenocarcinoma and adenoid cystic carcinoma are suspected. Adenoid cystic carcinomas are positive for CD117 in the inner epithelial cells and most pleomorphic adenomas are GFAP-positive.[13]

High-grade transformation is rare and is usually seen in recurrent tumours. In general, patients have a good survival outcome when addressed early and adequately. A local recurrence rate of 5.3–33% has been reported over a 5–10-year period. Cervical nodal metastasis has been documented to occur even years after primary tumour removal, highlighting the significance of elective neck dissection and adjuvant RT.[9] In some studies, a 4% local and regional recurrence rate was found and a minimum follow-up period of 15–20 years has been recommended.[12] Although most PACs are undeniably low-grade, the behaviour is unpredictable and can be equivalent to mucoepidermoid carcinoma, sometimes worse. According to Evans and Luna, 15% of cases had cervical metastases, 7.5% had distant metastases and 12.5% of patients died of disease.[15]

In our case, the histological characteristics of PAC warranted post-operative RT; however, the patient’s non-compliance was the possible reason for local recurrence within such a short duration of time (1.5 years). Thus, it is essential to highlight the importance of adjuvant RT in addition to sound surgical treatment for the optimal management of PAC. However, after a second surgery comprising of wide excision of the recurrent lesion in the buccal space and submandibular region, the patient has been on close follow-up for 6 months without any complications. We would like to emphasize on a few rarities of PAC that were noted in our case; these were the patient’s young age, symptomatic presentation, uncommon anatomic location (retro-maxilla), cervical nodal metastasis, perineural and skeletal muscle infiltration, and local recurrence within a short period of time. All this indicates the potentially aggressive nature of the otherwise indolent tumour and stresses the need for prompt and adequate management.

CONCLUSION

Although PAC is a low-grade tumour with excellent prognosis, it may occasionally present with invasive characteristics, and early diagnosis and prompt management with strict adherence to post-operative regimens and follow-up is of prime importance to prevent any untoward outcomes.

Consent

Written informed consent was obtained from the patient included in the article.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.