A total of 58 patients with ACC of the minor salivary glands of the palate were identified who had flap reconstruction following radical resection at the Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University (Guangzhou, Guangdong, China). Of the 58 patients, 28 were male and 30 were female. Patient age ranged from 20 to 80 years (median ± standard deviation, 49.2 ± 9.8 years). We classified patients into ≤ 60 years (n = 47) and > 60 years (n = 11) age groups according to the cut-off age for “elderly” recommended by the World Health Organization (WHO).9 All patients exhibited slow-growing, painless swelling of the palate that began several months prior. Tumors were classified according to size, i.e., as ≤ 2 cm (n = 9) or > 2 cm (n = 49). In all cases, histologic diagnosis was confirmed according to the 2017 WHO classifications for salivary gland tumors.10 ACC tumors were histopathologically classified as grade I–III. Grade I tumors showed a tubular and cribriform pattern without solid components (n =14) (Fig. 1); grade II tumors were cribriform with < 30% solid components (n = 18); and grade III tumors had ≥ 30% solid components (n = 24) (Fig. 2). Tumors with an area of histologic transformation were classified as transformed (n = 3).
Perineural invasion, bone invasion, and lymph node metastasis—which were defined as the presence of ACC cells in the nerve fiber (Fig. 3), maxillary bone (Fig. 4), and lymph nodes of the neck (Fig. 5) on histological examination—were noted in 48 (82.8%), 52 (89.7%), and 3 (5.2%) patients, respectively. According to the classifications of the American Joint Committee on Cancer’s Cancer Staging Manual (8th edition),11 9 (15.5%), 35 (60.3%), 11 (19.0%), and 3 patients (5.2%) had clinical stage I–IV disease, respectively.
Forty-four patients with early stage disease underwent radical excision, including subtotal maxillectomy (intraoral approach) and ipsilateral selective neck dissection. According to the Brown classification for maxillary and midface defects,12 44 patients had class II maxillary defects (requiring subtotal maxillectomy not involving the orbital floor or adnexa) that were reconstructed with a facial-submental artery island flap (FSAIF) based on the distal facial pedicle (Fig. 6). Fourteen patients with advanced-stage disease underwent radical excision, including total maxillectomy (via the Weber–Ferguson approach) with preservation of the orbital contents, and ipsilateral selective neck dissection. Class III maxillary defects (requiring total maxillectomy and loss of orbital support) were reconstructed with titanium mesh and a free anterolateral thigh flap (ALTF) (Fig. 7).
All submandibular lymph nodes were checked during flap elevation and confirmed as pathologically negative before we harvested the FSAIF. Details of the surgery were provided in a 2008 report.13 All intraoperative proximal margin frozen section (FS) specimens were classified as R0 (FS analysis showed negative surgical margins) or R1 (FS analysis showed negative surgical margins after previous identification of positive margins and additional resection). Resection status was R0 in 56 patients (96.6%) and R1 in 2 (3.4%). Fourteen patients with advanced-stage disease were treated with surgical excision followed by cobalt Co 60 adjuvant radiotherapy for the primary tumor site, and the interval between surgery and radiotherapy was 30 days. In total, 60 Gy was administered over 30 days with a conventional dose of 2 Gy fractions/day.
We used immunohistochemistry to analyze Ki-67 expression in paraffin‑embedded specimens obtained from 52 patients with ACC. Ki-67 expression was determined semiquantitatively based on the cytoplasm staining intensity and percentage of positively stained tumor cells.14 Staining intensity was scored as 0, indicating no staining or weak staining; 1, moderate staining; or 2, strong staining. The percentage of immunoreactive tumor cells was scored as 0, representing < 10% positivity (Fig. 1B); 1, 10–50%; or 2, > 50% (Fig. 2B). The overall Ki-67 expression score thus ranged from 0 to 4, i.e., the sum of the points for the percentage of positively stained cells and staining intensity. For statistical analysis, patients were divided into two groups: those with scores of 0–2 were considered to have low Ki-67 expression, and those with scores of 3–4 were considered to have high expression.8 Ki-67 expression was low in 40 patients (76.9%) and high in 12 patients (23.1%). However, high Ki-67 expression was identified in 3 of 28 patients (10.7%) with low-grade tumors and 9 of 24 patients (37.5%) with high-grade tumors. Table 1 summarizes the demographic and clinical characteristics of the patients with palatal ACC.
Table 1
Demographic characteristics, clinical characteristics and outcomes of 58 patients with palatal adenoid cystic carcinoma
Parameter | No. Of cases (%) | Survival without disease (%) | Survival with recurrence (%) | Death (%) | P-value |
Sex Male Female | 28 (48.3) 30 (51.7) | 19/28 (67.9) 22/30 (73.3) | 4/28(14.2) 5/30 (16.7) | 5/28 (17.9) 3/30 (10.0) | 0.683 |
Age (y) ≤ 60 years >60 years | 47 (81.0) 11 (19.0) | 32/47 (68.1) 9/11 (81.8) | 8/47 (17.0) 1/11 (9.1) | 7/47 (14.9) 1/11 (9.1) | 0.665 |
Tumor size (cm) ≤ 2 cm > 2 cm | 9 (15.5) 49 (84.5) | 9/9 (100.0) 32/49 (65.3) | 0/9 (00.0) 9/49 (18.4) | 0/9 (0.0) 8/49 (16.3) | 0.109 |
Histopathologic grade Low grade (I–II) High grade (III + transformed) | (14 +18) (55.2) (23 + 3) (44.8) | 30/32 (90.6) 11/26 (42.3) | 0/32 (0.00) 9/26 (34.6) | 2/32 (6.3) 6/26 (23.1) | 0.0001 |
Perineural invasion Absent Present | 10 (17.2) 48 (82.8) | 9/10 (90.0) 32/48 (66.6) | 1/10 (10.0) 8/48 (16.7) | 0/10 (0.0) 8/48 (16.7) | 0.281 |
Bone invasion Absent Present | 6 (10.3) 52 (89.7) | 6/6 (100.0) 35/52 (67.3) | 0/6 (00.0) 9/52 (17.3) | 0/6 (100.0) 8/52 (15.4) | 0.250 |
Lymph node metastasis Absent Present | 55 (94.8) 3 (5.2) | 41/55(74.6) 0/3 (0.0) | 7/55(12.7) 2/3 (66.7) | 7/55(12.7) 1/3 (33.3) | 0.015 |
TNM stage Early (I–II) Advanced (III–IV) | (9+35) (75.9) (11+3) (24.1) | 39/44 (88.7) 2/14 (14.3) | 2/44(4.5) 7/14 (50.0) | 3 /44(6.8) 5/14 (35.7) | 0.0001 |
Treatment Radical excision Radical excision with radiotherapy | 44 (75.9) 14 (24.1) | 36/44 (81.8) 5/14 (35.7) | 4/44 (9.1) 5/14 (35.7) | 4/44 (9.1) 4/14 (28.6) | 0.004 |
Surgical margin R0 R1 | 56 (96.6) 2 (3.4) | 41/56 (73.2) 0/2 (0.0) | 8/56 (14.3) 1/2 (50.0) | 7/56 (12.5) 1/2 (50.0) | 0.081 |
Ki-67 expression※ Low High | 40 (76.9) 12 (23.1) | 31/40 (77.5) 3/12 (25.0) | 5/40 (12.5) 4/12 (33.3) | 4/40 (10.0) 5/12 (41.7) | 0.003 |
※Determined in paraffin‑embedded specimens obtained from 52 patients. |
All patients underwent radical excision with wide safety margins of normal tissues and successful reconstruction of palate defects with a FSAIF or ALTF. No local or general complications developed. The median (range) follow-up duration was 32.9 (14–58) months. Forty-one (71.7%) patients survived without evidence of disease recurrence. Nine patients (15.5%) survived with recurrent tumors (including four with local recurrence [maxilla], three with regional recurrence [skull base] who underwent salvage surgery [Fig. 8], and two with distant metastasis [lungs]); among these patients, five had overlapping recurrence. Eight (13.8%) patients died of distant (two patients with brain metastasis and three with lung metastasis), or multiorgan metastasis (three with metastasis in the lungs and liver) between 22 and 42 months. The median (95% CI) OS was 32.5 (25.0–39.5) months, and the median (95% CI) PFS was 32.9 (28.5–36.9) months (Fig. 9).
Sex, age, tumor site, perineural invasion, bone invasion, and surgical margin status were not associated with survival or recurrence (P > 0.05). However, survival and recurrence rates differed according to histopathologic grade (i.e., between the low- and high-grade tumor groups) and TNM stage (i.e., between the stage I–II and stage III–IV disease groups) (P < 0.001). In addition, survival and recurrence rates differed according to lymph node metastasis (i.e., between those with and without metastasis), treatment (i.e., between those who received radical excision with versus without radiotherapy), and Ki-67 expression (i.e., between those with low and high expression) (P < 0.05). Patient outcomes are summarized in Table 1.