Sebaceous Carcinoma of the Submandibular Gland a Case Report and Review of the Literature

Sebaceous carcinoma (SC) generally develops in the periocular glands or skin, and carcinoma originating from the salivary glands is extremely rare.^1,2 The etiology and pathogenesis of SC are not yet clear, but they may be related to Muir–Torre syndrome (MTS), gene mutations, long-term ultraviolet (UV) damage, immunosuppression, or viral infections.^3–5 These tumors generally develop in middle-aged to elderly people; the mean age for extraocular SC is 65 years (range: 9–93 years), and no noteworthy gender predilection has been identified.^6–8 At early stages of this disease, the clinical manifestations of SC are nonspecific, which delays diagnosis and may result in increased metastasis and mortality. Therefore, it is critical to understand the epidemiology and biology of this rare cancer to improve early detection; however, at present, only about 50 cases of this rare cancer have been reported in the English literature.^9,10 Here, we report the case of a young-aged woman who was diagnosed with SC of the submandibular gland and review the relevant literature. The clinicopathological and immunohistochemical (IHC) features are also discussed.

Case Presentation

A 36-year-old woman presented to our institution in 2022 with the chief complaint of a non-tender solitary nodular mass in the left submandibular region that had developed more than 2 months prior. The patient had no fever, chills, cough, or other oral lesions. Her face showed basic symmetry and the overlying skin was normal in appearance. Anti-inflammatory drugs were administered orally, but no significant improvement was observed.

Physical examination revealed a 1.5×1 × 1 cm³ pea-sized firm, fixed mass with clear boundaries that was not encapsulated located on the inner side of the left submandibular gland region. The mass exerted no pressure effect on the surrounding organs. The patient had no remarkable medical or family history. No other abnormalities were observed in other organ systems. Laboratory examination revealed no abnormalities.

Computed tomography (CT) revealed that the left submandibular gland was slightly swollen and strongly enhanced in the intravenous contrast condition compared with the contralateral side. A nodular lesion in the left submandibular gland was observed with a diameter of approximately 1.2 cm, uniform reinforcement, and clear boundary (Figure 1A). The CT scan revealed no evidence of other lesions in the head or neck region. Ultrasound examination revealed a mixed-component nodule in the left submandibular gland (Figure 1B). The hypoechoic mass was rich in short rods and punctate blood flow signals.

Figure 1 Computed tomography scan showing an enhanced mass located in the left submandibular gland. Red arrows: sebaceous carcinoma mass (A). Ultrasound examination revealed a mixed-component nodule in the left submandibular gland (B).

Diffuse enlargement of the left submandibular gland was observed intraoperatively. The left submandibular gland was completely resected under general anesthesia, and the surgical margins were negative. Hematoxylin and eosin-stained sections of the surgical specimen revealed tumor cell nests infiltrating normal salivary gland tissues. Malignant cells were characterized by pleomorphic nuclei with prominent nucleoli and a moderate number of mitoses in the foamy cytoplasm (Figure 2A). There was evidence of perineural invasion (Figure 2B), but no significant vascular invasion was observed. IHC analysis of the specimen showed strong positivity for P63, P40, CK7, CK8/18, MLH1, PMS2, MSH2, and MSH6. The KI-67 labeling index was determined to be 15%. The partial area was positive for PAS and anti-epithelial membrane antigen (EMA). The tumor was negative for androgen receptor (AR), CEA, S-100, CK5/6, BCL-2, SOX-10, SOX-11, SMA, CD117, DOG-1, Galectin-3, GCDFP-15, and GFAP (Figure 2C–J).

Figure 2 ((A) ×200) Hematoxylin and eosin staining showing tumor cell nests infiltrating into the salivary gland tissues. Malignant cells show prominent nucleoli, nuclear atypia, and foamy cytoplasm. ((B) ×400) Perineural invasion was present in the tumor tissue. ((C) ×400) Immunohistochemical examination showed: negative staining for androgen receptor; ((D) ×400) positive staining for CK7; ((E) ×400) positive staining for epithelial membrane antigen (EMA) in focal areas; ((F) ×400) negative staining for GCDFP; ((G) ×400) KI-67 index of approximately 15%; ((H) ×400) positive staining for MLH1; ((I) ×400) positive staining for P63; ((J) ×400) negative staining for S-100.

The morphological and IHC findings were compatible with the diagnosis of SC. The patient is still undergoing follow-up, and at 2 months since diagnosis, no metastasis or recurrence has been observed.

Discussion

SC originating from the salivary glands is rare, and to date, approximately 50 cases have been reported in the English literature. Most of these occur in the parotid gland, and only five have been reported to originate from the submandibular gland.^6,11 The onset age of salivary gland SC has been reported to range from 9 to 93 years, with a bimodal age distribution (a minor peak in the 3rd decade and a major peak in the 6th and 7th decades).^8,12 The clinical data of salivary gland SC cases since 2010 are summarized in Table 1. Clinically, the symptoms of SC vary from an indolent, slow-growing, painless, solitary nodule to a painful, rapidly progressing swelling accompanied by facial paralysis. Therefore, it was frequently misdiagnosed as common benign conditions, resulting in delayed treatment and management. Risk factors for the development of SC include prior radiation exposure, MTS, immunosuppression, DNA mismatch repair, and long-term UV damage.^13,14 Suspected SC should be assessed based on the history of visceral malignancy and other risk factors.¹⁵ The lesion in this case occurred in the major salivary gland without past tumor history or risk factor exposure, making it difficult to diagnose. Additionally, the patient’s age was in the minor peak of the usual onset range, making the diagnosis more difficult.

Table 1 Reported Cases of Salivary Sebaceous Carcinoma (from 2010 to 2022)

Sebaceous gland tissue can be detected in the normal major salivary glands.⁶ However, the origin of sebocytes in the parotid gland is unclear. This may occur as a result of differentiation of pluripotent stem cells or ductal cells. SCs can be categorized into well-differentiated and poorly-differentiated varieties based on the extent of sebocyte differentiation.¹⁶ Poorly-differentiated lesions pose a challenge to pathologists as they lack any conspicuous sebocyte differentiation. Microscopic examination of the well-differentiated specimen showed that the sebocytes and duct epithelial cells formed many irregular, asymmetric sebaceous lobules. Typically, malignant cells exhibit significant cytoplasmic vacuolation and hyperchromatism.⁶ Pleomorphic cells further show variable degrees of mitotic activity and nuclear atypia.

Due to their origins and differentiation, there are histologic overlaps and discrepancies between different cases of SC (Table 2). IHC markers, such as GCDFP-15, EMA, AR, CK7, P40, P63, and adipophilin, can be helpful in confirming the diagnosis.^6,17,18 The P63 antibody typically stains myoepithelial and basal cells and the proliferative cells of the sebaceous glands. P40 is a short isoform target of P63 that can be utilized as a marker of the sebaceous lineage to evaluate sebocyte differentiation.¹⁸ One study examining periocular SC found that AR is useful in the diagnosis of poorly-differentiated tumors. Higher AR expression increases the risk of progression and recurrence, as circulating dihydrotestosterone promotes the growth of sebaceous glands.¹⁹ However, AR expression was negative in some metastatic salivary gland SCs.⁶ EMA is expressed primarily in the sebocytes in both the cytoplasm and membrane, but is negative in most basaloid peripheral cells. Extraocular SC is obviously correlated with mismatch repair (MMR) proteins (MSH2, MLH1, MSH6, and PMS2) in previous studies, suggesting that the MMR pathway is primarily responsible for the pathogenesis of SC.^20,21 Detection of MMR protein loss by IHC for SC diagnosis has a sensitivity of 81–85%.²² In this case, IHC staining showed normal nuclear expression of MLH1 and MSH2 in tumor cells; P40 and P63 were positive, and granular expression of EMA was observed. The tumor cells were negative for S-100 and AR, and the KI-67 proliferation index was approximately 15%.

Table 2 IHC Makers of Salivary Gland Sebaceous Carcinoma

Because several types of malignant tumors arise in the salivary glands, imaging examinations alone cannot lead to a histological diagnosis, but ultrasonography or CT scan of the lymph node region can be used to assess the recurrence or clinical stage. Salivary gland SC should also be distinguished from epithelial-myoepithelial carcinoma, poorly-differentiated squamous carcinoma, pleomorphic adenoma, mucoepidermoid tumors, and lymphadenoma or lymphadenocarcinoma. Surgical resection remains the primary treatment modality, although this results in a degree of functional and esthetic morbidity, and local recurrence and metastasis occur in a significant proportion of patients.^23,24 The role of radiation therapy in primary SC is uncertain. There is no specificity in the early stages of SC, thus requiring a high level of suspicion by clinicians for timely diagnosis and treatment. Metastatic spread can occur to either regional nodes or distant sites, such as the lungs and brain. Thus, close follow-up is critical to investigate potential recurrence.

Conclusions

This case highlights that any rapidly growing skin or subcutaneous mass should raise a suspicion of SC, although its incidence is low. The symptoms, signs, and CT examinations are not specific compared with those of carcinoids. Immediate biopsy or pathological detection is essential to ensure a timely diagnosis. Management options should be considered based on histological features as well as the extent of tumor spread for a favorable prognosis.