Patients suffering HCC with bone metastasis have a very poor survival rate; 1-year survival was 15–20%, and 2-year survival was only 4% [10]. Pesis et al. analyzed 41 patients from the English literature and reported that the average patient survival was 12.4 months after the diagnosis of primary HCC and 6.1 months after jaw metastasis [9]. In our study, we found a mean period of 71.9 months survival time after the diagnosis of primary HCC and a mean period of 16.9 months survival time after detection of OMHCC, which was a much better result than the previous report. There are two reasons to explain this difference. First, the time of the sample collection might have affected the survival. In the study of Pesis et al., patients were drawn from the literature published between 1940 and 2013; however, observation period of our patients is confined to the only last decade (2006~2016). The recent advancement of medical technology might have enabled early detection and intervention of involved region. Recent report by the National Cancer Institute in the USA showed that the 5-year relative survival rates for liver cancer were 5.6%, 8.5%, 11.2%, 15.3%, and 18.1% from 1993–1995, 1996–1998, 1999–2001, 2002–2005, and 2006–2012, respectively [11]. It reflected the progress in cancer therapy, and the data showed better results year by year. Second, the location of the sample collection would have influenced the survival. The epidemiology of HCC varies from country to country [12]. Especially, the relative contribution of HBV and HCV to HCC varies substantially country by country [13]. In this study, there were nine patients who could be classified as HBV-related HCC and one patient as alcoholic liver disease-related HCC. In South Korea, one study reported that the underlying liver diseases of HCC patients included HBV (72.3%), HCV (11.6%), alcoholic liver disease in (10.4%), and non-B non-C hepatitis (0.7%) [14,15,16]. Our case is consistent with this report. In the USA, another study reveals that the underlying liver diseases of HCC patients included hepatitis B (23%), hepatitis C (39%), alcoholic liver disease in (21%), and non-B non-C hepatitis (12%) [17] Diagnostic and management methods such as medication, vaccination, and detection of cirrhotic liver are influenced by these hepatitis types [18]. Early detection of tumor through proper diagnosis and surveillance is critical to patient survival. Variation in management including treatment patterns throughout the world and whether the nation had government-funded or national surveillance programs would be also sequential to patients’ survival.
In spite of the longer survival time than previously reported, 16.9 months is not enough time for the patients diagnosed with OMHCC. A poor prognosis should be noticed to the patients and their family. Among 10 patients, four underwent palliative surgery to control the oral lesion and others not. Patients who underwent palliative oral surgery lived more (35.5 months) than the others who did not received operation (4.5 months). Although there was no statistically significant difference (p = 0.059) in mean survival time between the two groups due to the limited sample size (n=10), huge difference in survival time (31.0 months) existed. That might have come from the decision-making process. When we decide to do the surgery or not, the main reason for not performing the surgery was that the surgery would not help the patient’s survival. Collaboration with oncologist is always recommended because the life expectancy of OMHCC patients is often very short.
Before deciding to perform the palliative surgery or not, the risk of surgery should be evaluated by appropriate clinical examination. Palliative surgery should be performed when the benefit is way superior to the risk. The decision for operation should be made based on the clinical examination of patients’ both oncologist and oral and maxillofacial surgeon. The main reason and inclusion criteria for operation are (1) spontaneous bleeding which might jeopardize the patient unless treated, (2) movable mass which makes it difficult to chew and swallow, (3) severe pain, and (4) single metastasis from HCC. When it comes to OMHCC, the risk of massive bleeding is always present. Metastasis from HCC has been reported as a hemorrhagic tumor because of its hypervascular nature [19]. Furthermore, in view of the coagulopathy that often accompanies primary liver disease, a resection or even a biopsy can be complicated by hemorrhage. In our cases, there was no severe coagulopathy. The INR (Internationalized Normalized Ratio) of all patients ranged from 0.94 to 1.21. However, all four patients undergoing surgery had a large amount of bleeding. Meticulous bleeding control was always required.
In our cases, there was just 1 case that oral lesion was the first manifestation of MHCC. In other 9 patients, they already had some metastatic lesion other than oral site. This means that proper management on oral lesion could not increase patients’ survival rate dramatically in 9 cases. However, in case 6 which was oral lesion as first manifestation of metastasis from HCC shows longest survival times (63 months). It seemed that proper management of oral lesion was beneficial to the patient survival time. In a previous review including 390 metastatic tumors to the jaw bones, the average time between the diagnosis of the primary tumor and appearance of the jawbone metastases was estimated to be 39.5 months [20]. It is similar as our cases which show that the average time between the diagnosis of the primary HCC and the diagnosis of the OMHCC was 43.1 ± 50.5 months. Among 10 patients, 6 patients received radiotherapy on OMHCC with total dose ranged from 35 to 60 Gy. Radiotherapy is generally considered effective for metastatic bone cancer, and there are reports concerning the effects of radiotherapy on bone metastases from HCC [21]. In a recent study of radiotherapy on metastasis from HCC, total dose ranged from 12.5 to 66 Gy resulted in pain relief rate from 73 to 99.5% and improvement of the patient’s quality of life [22]. The 1-year survival rate after radiotherapy initiation or the diagnosis of bone metastasis of HCC has been reported to be 13.8–32.4%, with a 5–7.4 months’ median survival time [7, 8, 23]. In our cases, the median survival time of patients treated with radiotherapy for oral lesion was 5 months. It is same as the result above. However, in our cases, due to the limited sample number (n=10) and multifactorial effect on patient survival, there was no significant difference between the group treated with oral radiotherapy or not (Log-rank 0.27; p > 0.05).
Except one patient due to the side effect of anti-cancer drug (azotemia), 9 patients were on systematic chemotherapy (6 patients treated with sorafenib, 1 patient sunitinib, 1 patient cisplatin, 1 patient 5-fluorouracil). Again, in our cases, due to the limited sample number (n=10) and multifactorial effect on patient survival, it is difficult to evaluate the relationship between kind of systemic chemotherapy and patient survival in OMHCC cases. There was a certain male predilection (8 men and 2 women), and this corresponds with the male predominance of HCC. Rates of liver cancer among men are two to four times as high as the rates among women [2]. Patient age ranged from 40 to 71 years (mean 56.5, median 57.5) in this study. In case of HCC, the greatest proportional increase has been seen among Hispanics and Whites between 45 and 60 years of age [24]. It is also similar to the mean age of all head and neck metastases [25]. The most often encountered chief complaint was swelling (80%) followed by pain (60%), numbness (60%), bleeding (10%), and tooth mobility (10%). This corresponds with the recent study of metastasis from HCC to the jaw bone [9]. Metastasis from HCC to the jaw is very rare. When it does occur, the most frequently affected site is the mandible [26]. Among 10 OMHCC cases, the mandibular were affected in 9 cases (90%), and there was a significant predilection over maxilla (10%). In 9 mandibular OMHCCs, seven were posterior and two were anterior lesion. However, in the maxillary lesion, it was located in the middle part of hard palate anterior-posteriorly. The mean size of OMHCC was 3.3 ± 1.8 cm which measured in their largest diameter ranged from 0.8 to 7.2 cm. This corresponds with the recent study about OMHCC to the jaw bone reporting that the size of lesion ranged from 0.2 to 9 cm (mean 3.95) [9].
Generally, in metastatic tumors to the jaw bone, the mandible was the most common location (82%) with the molar area being the most frequently involved site [27]. This is because the mandible contains hematopoietic tissue especially in the posterior mandible [19]. Several pathways of HCC metastasis to the jaw have been suggested. Among them, hematogenous pathway is widely accepted; the tumor reaches the circulation through invasion of the hepatic arterial and/or portal venous branches. Most jaw metastases are associated with lung metastases, and they possibly occur by this route [28]. In our cases of OMHCC, the most often site other than oral site was the lung (7), followed by bone (4), adrenal gland (2), brain (2), buttock (1), and abdomen (1). In a recent study including 398 HCC autopsies, extrahepatic metastasis was found in 156 of 398 HCC (39.1%), with lung metastasis (74.5%) being the most common, followed by the bones (24.8%) and adrenal glands (19.1%) [29]. The proposed pathway of metastasis above corresponds to these results.
The Batson venous plexus is a network of valveless veins that connect the deep pelvic veins and thoracic veins to the internal vertebral venous plexuses. Metastatic HCC cells can reach the mandible through the Batson plexus bypassing the pulmonary, inferior caval and portal venous circulations. This pathway may be responsible for metastasis to the vertebral bodies, which are the preferred site of bony HCC metastasis. This could be the most likely pathway from HCC without pulmonary metastasis as appeared in 3 of 10 cases in this study. There were some cases that showed the relationship with oral surgery and tumor growth stimulation. In our patients, cases 6 and 8 who underwent many oral palliative surgeries suffered from tumor recurrence in surgical margin. Also, MHCC in case 9 emerged from surgical extraction of the right mandibular third molar.
