Ⅰ. INTRODUCTION

Mucinous adenocarcinoma (MAC) refers to a malignant neoplasm that falls under a subtype of adenocarcinoma which mostly develops in the digestive system¹⁾ and produces mucin^2,3). According to the World Health Organization (WHO) classification on tumors of the head and neck (2005), MAC is classified as a tumor of salivary gland origin. Histologically, MAC is formed by clusters of epithelial cells floating in large volume of mucin pools. It is mainly described as “single cancer cells and their clusters floating in huge extracellular mucin pools separated by fibrous walls”⁴⁾.

Clinically, MAC is an exophytic mass that is sometimes suspected as a benign tumor because of its painless and steady growth. However, it frequently recurs locally and spreads to the cervical lymph node (LN) and other organs. According to some reports, approximately half of the patients with MAC die within 6 years of the onset^5,6).

Cases of MAC of intraoral minor or major salivary gland origin are extremely rare. The palate and sublingual gland are regions in which this type of MAC most commonly occurs, followed by the submandibular gland and upper lip^3,4,7). Because of the rarity of this tumor, its accurate incidence is unknown. Although still under debate, the tumor is estimated to account for approximately 0.1% of all cases of sialoma⁵⁾. In addition, little information is available regarding the treatment method and prognosis of MAC of salivary gland origin because of its rarity. Accordingly, in this study, we aimed to evaluate the clinical characteristics, treatment methods, and prognosis of MAC of salivary gland origin as reported in the current literature. In doing so, the study also attempts to predict changes in the prognosis of MAC, depending on the occurrence of LN metastasis. In addition, we will introduce a case of MAC of minor salivary gland origin in the patient’s oral commissure.

Ⅱ. METHODS

We extracted data from the PubMed and Google Scholar until March 2019. In accordance with the purpose of this study, only cases of MAC of intraoral minor and major salivary gland origin were included. Non-English articles and journals with insufficient information were excluded. However, if English abstracts of some non-English articles provided relevant information, they were included to the cases selected for this study.

The keywords for our journal search with the MeSH term were “adenocarcinoma, Mucinous”[MeSH] AND [(oral*) OR (mucosa) OR (salivary) OR (gland)]. Initially, 802 articles were retrieved. Among them, 789 journals were excluded for irrelevancy after a review of their titles and abstracts. Four out of the remaining 13 studies were excluded because they were non-English articles. Moreover, 469 articles were retrieved using the keywords “mucinous adenocarcinoma” AND (oral, OR mucus, OR saliva, OR gland), and eight unduplicated articles were added after a review on titles and abstracts. The main body of one article was not written in English, but contained sufficient information in its English abstract and was, thus, included in the final set of articles. Two authors of this study independently retrieved and evaluated the literature. In case of a dispute, they reached a consensus through discussion. (Fig. 1)

Finally, a total of 19 cases out of 17 articles were selected from the existing literature and a new case was added and described in the present report. Extracted data regarding the total 20 cases covered details such as age, sex, the region of origin, clinical characteristics, metastasis, treatment methods, prognosis, and observation period. Later, six cases that did not accurately describe prognosis or include treatment were excluded when investigating correlations between LN metastasis and the prognosis of the disease. (Table 1)

Ⅲ. RESULTS

1. Clinical features

The mean age of the patients with MAC of intraoral origin was 66.9 (47–82) years. The ratio of men to women was 2.3:1 (14:6), showing a higher incidence in men than in women. In terms of regions of origin, tumors in 4 out of the 20 cases were MAC of major gland origin and in 16 cases, they were of minor gland origin. With respect to the types of major glands, in two cases, the tumor was of the parotid gland origin and in one case each, it was of the submandibular and sublingual gland origin. With respect to the types of minor glands, the palate was the most common region (five cases), followed by the buccal mucosa (four cases) and the gingiva (two cases). In addition, the tumor was reported to arise from the upper lip, lower lip, ventral surface of tongue, and mouth floor in one case each. Moreover, in one case, the tumor had a temporomandibular joint origin.

In terms of clinical appearances, most cases showed hard, protuberant and painless lesions, whereas some cases complained of dull pain. In three cases, patients experienced abnormal senses because of neural invasion in adjacent areas. The reviewed lesions showed an overall pattern of relatively slow growth. In eight cases, the patients had been misdiagnosed with benign lesions during clinical diagnosis prior to a biopsy^7,8-12).

2. Treatment modality

In 18 of the 20 cases, wide surgical resection was performed and in 9 of these 18 cases, neck dissection was performed. In two cases, neck dissection was performed as a preventive measure, even though based on clinical and radiological findings, LN metastasis was not observed^11,12). Radiotherapy was conducted in two cases preoperatively and in four cases postoperatively^{6,10,11,13-15)}. Chemotherapy for MAC was performed in two cases^1,16).

3. Metastasis and prognosis

Of the total 20 cases, information on whether the patients survived or developed metastasis was not reported for two cases^14,17). In addition, one case was excluded because of unclear summary on patient’s metastasis and prognosis because of continuous recurrences and absence of follow-up treatment¹⁾.

Of the remaining 17 cases, 10 cases reported survival of patients during follow-up, and only two patients among these experienced recurrences. Seven cases reported the death of the patient. Of the 10 patients that survived, six showed early-stage (stage 1 or 2) oral cancer, two were at stage 3, and one was at stage 4a. In one patient, the cancer stage was not clear¹⁵⁾.

Among the seven patients who died, two did not undergo treatment and one died of MAC in the pancreas 3 years later, which was unrelated to the MAC of salivary gland origin. Of the four patients who died despite treatment, one was at stage 1 and three were at stage 4a.

To identify the relationship between LN metastasis and the prognosis of MAC, one case of death due to MAC at the pancreas 3 years later, unrelated to the MAC of salivary gland origin, was excluded from the 17 cases that reported on metastasis and prognosis. Two patients who died after refusing treatment were also excluded.

Of the remaining 14 cases, six patients were confirmed to have LN metastasis at their first hospital visit and only one patient was found to have LN metastasis postoperatively¹⁸⁾. Among the six patients with LN metastasis, four died within 2–29 months of the onset of metastasis. One of the two surviving patients is the subject of this study who has survived over the 24-month follow-up, whereas the other patient experienced recurrence of MAC in the cervical LN 6 months later.

Of the 10 patients who survived, eight patients did not show LN metastasis at the first diagnosis. All of the four patients who died later showed LN metastasis at the first diagnosis.(Table 2)

Seven of the eight patients, who showed no recurrence or metastasis during the follow-up after a single surgery, did not have LN metastasis at the first diagnosis. Follow-up periods for the 14 cases ranged from 2 to 72 (average, 24.5) months, and some cases had a short follow-up period.

4. Case report

An 82-year-old female patient visited the department of internal medicine at a local hospital because of an approximately 1.5-cm-diameter mass around the oral commissure of her left lower lip. It was first misdiagnosed as a benign tumor, and thus, an excisional biopsy was performed on the affected region. However, it was later diagnosed as a malignant tumor, and the patient visited the Department of Oral and Maxillofacial Surgery at the Dental Hospital of Chonbuk University. Although the results of a magnetic resonance imaging could not identify a clear lesion in the area of primary focus because of the prior biopsy, one necrotic LN was present on the same left side at Level II, which suggested the likelihood of metastasis preoperatively. The results of fluorodeoxyglucose (FDG) positron emission tomography/computed tomography, showed a 1.3-cm nodule without FDG intake in the right lower lobe of the lung. In addition, a lung biopsy was performed, resulting in the diagnosis of chondroid hamartoma, which was irrelevant to the lesion in the mandibular angle.

Because results of the first biopsy were not definite, an ultrasound-guided fine needle aspiration was performed, and (r/o) mucoepidermoid carcinoma was diagnosed. Accordingly, wide surgical excision and supraomohyoid neck dissection were performed on the same side. Results of a final histopathological examination led to the diagnosis of MAC of minor salivary gland origin and confirmed the presence of LN metastasis.

According to histological findings, some of the lesions were covered with skin and its appendages such as hair follicles and sebaceous glands and other lesions showed minor salivary gland tissues in the oral mucous membrane and the lower part of the membrane. Lesions were found in the deep part between the two sides of tissues. Tumor cells had cylindrical-shaped clear cytoplasm containing mucus and elliptical-shaped nuclei. The nuclei of tumor cells appeared atypical, and cell division was rarely observed. The tumor cells showed a pattern of forming secondary lumens, and the cells producing mucus were projecting into mucous pools in a papillary pattern, which may be the most identical finding with “MAC of minor salivary gland origin”¹⁹⁾. (Fig. 2–5) Fig. 3, 4

Ⅳ. DISCUSSION

1. Frequency

MAC is known to mostly occur in the colon, appendix, lung, and ovary²⁾. MAC of salivary gland origin is extremely rare. Although it mainly occurs inside the mouth, it may also appear in TMJ or the ramus of the mandible^8,20).

A study reported that salivary gland malignancy accounted for 6% of malignancies in the head and neck, which is equivalent to 0.3% of all malignancies in the body⁴⁾. Tian et al. conducted a large-scale study on intraoral salivary gland neoplasms and reported that MAC comprised 0.13% (9/6982) of salivary gland tumors and 0.4% (9/2239) of malignant salivary gland tumors⁵⁾. Li et al. reported that MAC accounted for 0.07% (1/1392) of malignant salivary gland tumors in West China²¹⁾. Pires et al. studied minor salivary gland tumors within the United States and reported that MAC accounted for 0.2% (1/546) of all tumors and 0.4% (1/241) of malignant tumors²²⁾.

2. Age and gender ratio

The main age group with MAC includes individuals in their 50s and 60s. The incidence of the disease in men is reported to be approximately 1.5–3 times higher than that in women^1,7,9). In a review on approximately 40 cases on MAC arising form the salivary gland, Mezmezian et al. reported that it more frequently occurred in men (72%) than in women. The mean age of the patients was 57 years, and the youngest patient was 47 years old¹⁹⁾.

Seoane et al. studied MAC in the palatal and reported that the mean age of patients was 57.5 years and the ratio of men to women was 3:1, showing a higher incidence in men⁹⁾.

A study by Ide also showed that MAC of intraoral origin usually occurred in a relatively older age group (mean age of 64.6 years). The ratio of men to women was 1.4:1, showing a slightly higher incidence in men⁷⁾.

3. Region of origin

According to WHO, MAC of salivary gland origin most frequently arises from the palate and sublingual gland, followed by the submandibular gland and upper lip. The parotid gland is reported to be the region in which the disease occurs least frequently⁴⁾.

According to Mezmezian’s literature review on 40 cases of MAC of salivary gland origin, the disease occurred in the palate (14 cases), parotid gland (7 cases), submandibular duct (3 cases), mouth floor (4 cases), lips (3 cases), tongue (2 cases), pharynx (1 case), and buccal mucosa (6 cases)¹⁹⁾.

4. Clinical features

In term of clinical characteristics, MAC of salivary gland origin is a painless neoplasm that shows a pattern of outward growth similar to an adenoma, fibroma, or pyogenic granuloma³⁾. This characteristic led to the initial misdiagnosis of MAC of salivary gland origin as a benign mass in 8 of the 20 cases studied.

5. Prognosis

Ide reported that local recurrences and metastasis to the cervical LN or other organs occurred in 33%, 63%, and 29%, respectively, of the total 21 cases of MAC of minor salivary gland origin⁷⁾. In addition, 47% patients died within 6 years, and 57% of them were found to have metastasis to the cervical region at the time of clinical diagnosis.

Mezmezian reported that these tumors had an aggressive nature of LN metastasis and local recurrences, and approximately half of these patients died within 6 years of the diagnosis¹⁹⁾.

6. Histological features

The histological feature of MAC can be said to be “single cancer cells and their clusters floating in huge extracellular mucin pools separated by fibrous walls”^4,9). This tumor comprises round and irregular-shaped neoplastic epithelial cell nests or clusters floating in mucus-filled cystic cavities separated by connective fibrous strands⁴⁾. These tumor cells often show clear cytoplasms and darkly stained nuclei. Mitotic figures are sparse^3,4). Tumor cells are arranged in solid clusters and tend to form secondary lumens or incomplete duct-like structures. Mucus-producing cells may arrange in a papillary pattern projecting into the mucous pools⁴⁾. In their adjacent tissues, the proliferation of minor salivary glands can be observed, and this finding leads to suspect MAC of minor salivary gland origin³⁾.

In addition, intracellular and extracellular mucin components stain positively with periodic acid Schiff, Alcian blue, and mucicarmine stains^4,6). However, this staining feature is also observed with other salivary gland tumors.

7. Immunohistochemical method

The immunohistochemical staining method is helpful for differential diagnosis. Typical MAC is positive for cytokeratins (CK) AE1/AE3 and 7 and reacts moderately or highly with CK7, 8, 18, and191,4). CK 5/6, 10, 14, and 17 and smooth muscle actin are not stained (negative staining)¹⁾.

In addition, there is a difference in DNA copy number aberrations between MAC of minor salivary gland origin and that of colorectal origin¹⁸⁾.

8. Differential diagnosis

The diagnosis of MAC of salivary gland origin requires differential diagnosis from other conditions such as mucoepidermoid carcinoma, mucin-rich salivary duct carcinoma, and cystadenocarcinoma^1,3,11). Although mucoepidermoid carcinoma shows extracellular mucin, it is differentiated from MAC by its epidermoid pattern of tumor cells^6,9) and was not found in the present case study. Cystadenocarcinoma shows cystic spaces lined by epithelial cells. It differs from MAC where cystic spaces are present but not lined by the epithelium. In addition, a study describes the occasion presence of mucous, clear cells⁴⁾ unlike the findings of the present case. Although mucin-rich salivary duct carcinoma shows typical patterns of salivary duct carcinoma and comedo necrosis^4,9,23), the present case did not show these patterns.

9. Treatment method

Major treatment methods for MAC of intraoral origin include resection and neck dissection. The effects of chemotherapy and radiotherapy are still unclear^1,13).

10. Metastasis & prognosis

Because MAC of intraoral origin is extremely rare, little research has been done on its prognosis. The WHO mentioned about high likelihood of its local recurrence and local LN metastasis⁴⁾. Lukka noted that the stage of salivary gland cancer is an important factor in determining its prognosis. In their studies on salivary gland tumors, Bhat et al and Guimarães et al argued that the clinical stage of MAC is an important prognostic factor^3,11,24).

However, the cancer stage is a combined result of various elements such as tumor size, local LN metastasis, and metastasis to other organs. In particular, few studies have focused on prognostic factors of MAC of intraoral origin.

The present systematic review suggested that among stages of cancer, LN metastasis is a particularly important factor in determining the prognosis of MAC of intraoral origin. Given the limited number of cases and short observation period of this study, it is difficult to assert that the absence of LN metastasis leads to a higher survival rate or a longer survival time. However, the following results still imply that LN metastasis increases the likelihood of death because of subsequent metastasis from the LN and recurrences.

The mean mass size in the reported cases was 3.2 (1.2–7.6) cm. The cancer stage is determined based on combinations of tumor size, local LN metastasis, and metastasis to other organs. At the time of observation, most masses were relatively small-sized, probably owing to early detectability of the neoplasm in this region compared with that of neoplasms in other regions given the nature of the oral and maxillofacial area, Only one case of metastasis to another organ was observed at the first diagnosis⁸⁾.

Eventually, this result suggests that LN metastasis is an important prognostic factor of clinical stages of respective disease. This fact can help establish treatment plans with respect to the need of performing neck dissection and wide excision after the diagnosis of MAC.

In other words, it should be considered that MAC is highly prone to local recurrences and LN metastasis even after mass removal4), and once LN metastasis occurs, it increases the risk of death because of recurrences in LN and metastasis to the other organs even after neck dissection. Even if the first diagnosis shows only a small-sized MAC in an early stage as well as the absence of LN metastasis on the results of clinical and imaging tests, elective neck dissection (preventive neck dissection) should still be considered. If it is not performed, a close observation is required.

Ⅴ. CONCLUSION

MAC is an extremely rare salivary gland tumor with a high likelihood of local recurrence and LN metastasis⁴⁾. For treatment, it requires extensive resection coupled with neck dissection. Effects of radiotherapy and chemotherapy have not yet been verified. Like other salivary gland tumors, the prognosis of MAC depends on its clinical stage. In particular, local LN metastasis is an important prognostic factor. For this reason, elective neck dissection should be primarily considered when establishing treatment plans for MAC.