Synchronous Multifocal Canalicular Adenomas

Abstract

Canalicular adenoma (CAD) is an uncommon benign tumor of minor salivary glands with predilection for the upper labial mucosa. An 80-year-old female presented with nine submucosal nodules of the upper labial mucosa and bilateral buccal mucosa. Histopathologic examination revealed multifocal circumscribed tumor islands with a tubular growth pattern within a loose hypocellular myxoid background stroma. Interconnecting rows of columnar tumor cells imparted a canalicular morphology. In addition to the characteristic histopathologic findings, a comprehensive immunohistochemical panel supported a final diagnosis of multifocal CAD. Synchronous multifocality in CAD is an infrequent finding and this sine qua non clinicopathologic correlation article exemplifies such a case.

History and Clinical Findings

An 80-year-old female, current smoker, with hypertension, hyperlipidemia, depression, history of breast cancer status post radiation therapy (6 years prior), history of deep vein thrombosis (5 years prior), and history of right knee replacement (3 years prior) presented to the Oral Medicine Department of the University of Western Australia, Dental School, for an initial consult. Intraoral examination was significant for nine submucosal nodules of the upper labial mucosa and bilateral buccal mucosa measuring approximately 7–11 mm each (Fig. 1a–c). The nodules were covered with normal-appearing mucosa and were firm, mobile, and waxy in texture. Magnetic resonance imaging (MRI) of the maxillofacial region and skull base was significant for several nonspecific cystic lesions in the upper labial and buccal mucosa with a working diagnosis of retention cysts (Fig. 2a, b). Excisional biopsy of the three upper labial mucosa nodules was performed under local anaesthesia following informed consent. Subsequently, the patient was referred to the Oral and Maxillofacial Surgery Department of the University of Western Australia for removal of the remaining nodules under general anaesthesia after obtaining informed consent for the procedure (Fig. 3).

Fig. 1.

Clinical examination. The patient presented with nine submucosal nodules of the upper labial mucosa (b) and bilateral buccal mucosa (a, c) measuring approximately 7–11 mm each

Fig. 2.

Imaging studies. Fat-saturation T2 axial (a) and coronal (b) magnetic resonance scans. There are multiple small (2–8 mm) hyperintense foci (white dotted arrows) within soft tissue situated predominantly labial or buccal to the maxilla and to a lesser extent, the mandible

Fig. 3.

Surgical excision. Intraoperative photo showing removal of an encapsulated tumor from the upper labial mucosa

Diagnosis and Treatment

Histopathologic examination of all excised specimens revealed multifocal circumscribed tumor islands that were variably encapsulated, admixed with solid and cystic areas (Fig. 4a, b). Tumor islands displayed a tubular growth pattern within a loose hypocellular myxoid background stroma (Fig. 4c). Interconnecting rows of columnar tumor cells imparting a canalicular morphology were observed (Fig. 4d). Pseudostratification of the nuclei with a palisaded configuration eliciting reverse nuclear polarization away from tumoral lumens were prominent (Fig. 4e). Few isolated microliths were identified, and areas of cystic change with associated hemorrhage and scattered siderophages were also noted. Intraluminal squamous morules were evident (Fig. 4f). There was no evidence of necrosis, cytologic atypia, or mitotic figures.

Fig. 4.

Histopathologic examination. a Multifocal circumscribed tumor islands (H&E, × 6). b Cystic areas (H&E, × 40), c tubular growth pattern within a loose hypocellular myxoid background stroma (H&E, × 100). d Interconnecting rows of columnar tumor cells imparting a canalicular morphology (H&E, × 200). e Pseudostratification (H&E, × 200). f Intraluminal squamous morules. No evidence of necrosis, cytologic atypia, or mitotic figures (H&E, × 400)

Immunohistochemical stains for CK-7, SOX-10, and S-100 showed strong diffuse positive immunoreactivity (Fig. 5a–c). In addition, GFAP demonstrated diffuse weak positivity (Fig. 5d). Scattered diffuse weak positivity was seen for p63 (Fig. 5e). Calponin, DOG1, and p40 were all negative (Fig. 3f, h, i). Ki-67 was positive in approximately 1% of tumor islands (Fig. 5g). CK5/6 and p16 highlighted strong focal positivity for intraluminal squamous morules (Fig. 5j–k). The histopathologic and immunohistochemical features established a final diagnosis of multifocal CAD.

Fig. 5.

Immunohistochemical (IHC) characterization. a CK-7, strong diffuse positivity (IHC stain, × 20). b SOX-10, strong diffuse positivity (IHC stain, × 20). c S-100, strong diffuse positivity (IHC stain, × 40). d GFAP, diffuse weak positivity (IHC stain, × 40). e p63, scattered diffuse weak positivity (IHC stain, × 100). f Calponin, negative (IHC stain, × 200). g Ki-67 positive in 1% of tumor cells (IHC stain, × 100). h DOG1, negative (IHC stain, × 100). i p40, negative (IHC stain, × 100). j CK5/6 and k p16, strong focal positivity for intraluminal squamous morules (IHC stain, × 400)

All tumor nodules were treated via complete excision utilizing extracapsular dissection with variable cuff of soft tissue. The patient reported uneventful recovery at 4-week post-op follow up with no signs of recurrence.

Discussion

Canalicular adenoma (CAD) is an uncommon benign tumor of salivary glands accounting for 0.5–12% of all minor salivary gland tumors [1]. In the past few decades, CAD has been attributed to a terminal duct origin, defined as a monomorphic adenoma, and considered as a variant of basal cell adenoma [2, 3]. However, the most recent World Health Organization (WHO) classification defines CAD as a distinct “benign salivary gland tumor composed of monomorphous epithelial ductal cells arranged in anastomosing cords within cell-poor vascular stroma” [1]. CAD usually presents as a single, firm nodule, most commonly involving the upper labial mucosa (~ 80%), followed by the buccal mucosa, and rarely the palatal mucosa [1]. CAD is most commonly seen in the fourth to seventh decade with a female predilection [3].

Synchronous multifocality in CAD is an infrequent finding and occurs in only 9% of cases [4]. Interestingly, our case demonstrated multifocality with several separate nodules identified involving the bilateral buccal mucosa, and the upper labial mucosa. Although the excisional biopsies of the initial three upper labial mucosa nodules performed under local anaesthesia were histopathologically consistent with CAD, given the unusual presentation, removal of all of the remaining nodules were indicated. Although multifocality of basal cell adenoma has been reported in Brooke-Spiegler syndrome, intriguingly, there have been no reports of multifocal CAD associated with this syndrome. Moreover, CAD has not been associated with any other syndrome or inherited condition [4].

The main histopathologic differential diagnoses include basal cell adenoma, pleomorphic adenoma, polymorphous adenocarcinoma, and adenoid cystic carcinoma. Basal cell adenoma features a dual cell population, exhibits reduplicated basement membrane material, and does not display a canalicular architecture. Pleomorphic adenoma is pleomorphic in nature and features many different cell populations that include ductal, spindle, and plasmacytoid myoepithelial cells that blend into the stroma. The stroma in pleomorphic adenoma is often distinctively chondroid. Polymorphous adenocarcinoma is characterized by a single cell population, also imparts a pleomorphic appearance, but exhibits single cell filing and often displays tumor cells arranged in a targetoid concentric appearance. Adenoid cystic carcinoma demonstrates a biphasic phenotype and is infiltrative with frequent perineural invasion, has angulated nuclei and demonstrates numerous easily identifiable mitotic figures.

A consistent and validated reliable panel of immunohistochemical (IHC) staining for CADs has been lacking, however fortunately, Thompson et al. in 2015 established a comprehensive IHC panel for CADs [4]. In their retrospective study, 52 cases of CADs were comprehensively characterized by IHC. All cases demonstrated positivity for pan-cytokeratin, S-100, SOX-10, CK-7, CAM5.2, and E-Cadherin. Similarly, in our present case, CK-7, SOX-10, and S-100 were all diffusely strongly positive. In addition, GFAP was diffusely positive, which was a finding in 81% of cases analyzed by Thompson et al. in 2015.

Once a diagnosis of CAD is established, local excision is curative and the prognosis is excellent. Higher recurrence rates have however been reported in multifocal CAD and it has been suggested that this increased recurrence rate may not reflect a true recurrence but more likely can be attributed to multifocality and to the persistence of growth of microscopic foci that may extend beyond the margins of clinically-visible resected tumors [5, 6].

Compliance with Ethical Standards

Conflict of interest

The authors have no disclosures or conflict of interest to declare.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of retrospective case report, formal consent is not required. The tumor tissue included in the manuscript was obtained as part of the standard of care for the patient and retrospectively collected for the case report.

Informed Consent

No identifiable information is included in the case report, and the study meets the waiver criteria for the institutional review board of University of Western Australia.