Metastatic hepatocellular carcinoma to the parotid gland Associated with multiple metastasis: Case report

Introduction: The incidence of liver cancer is very high in China, and it is more common in patients with a history of hepatitis B.Most patients with liver cancer have distant metastasis at the time of visiting, but parotid metastasis is very rare. We report a patient with parotid enlargement who was diagnosed with multiple metastasis of liver cancer. Presentation of Case: A 52-year-old male presented with parotid enlargement for one month.after the right deep maxillofacial neck mass was cut and biopsied,Metastatic hepatocellular carcinoma of the parotid gland associated with multiple metastasis was diagnosed. Discussion: Metastasis of liver cancer to the parotid gland is very rare, to date, only 7 cases HCC metastasis to the parotid gland have been reported, this case is the rst report in China. For patients with parotid enlargement at the rst diagnosis, no history of hepatitis or liver cancer, and normal or slightly elevated AFP,It is very easy to misdiagnose and miss diagnosis.Pathological diagnosis and complete systemic examination are very important in the diagnosis of tumor.Although very rare, parotid metastases in HCC should be maintained with high suspicion. This paper reports a case report of a male patient with IV-stage hepatocellular carcinoma (stage D according to Barcelona Clinic of Liver Cancer, BCLC, staging classication) with right parotid gland metastasis, complicated with lung metastasis, Multiple mediastinal lymph nodes and the right lobe of the liver,Right adrenal nodule metastasis.which is the rst case reported in China.The patient was treated for parotid gland enlargement, and the pathological diagnosis was made by parotid gland tissue resection and pathological biopsy.Ki67 (about + 70%),AFP is slight increase, the patient was diagnosed hepatitis B for the rst time during the rst diagnosis and hospitalization.The tumor recurred in the postoperative site of parotid gland 22 days after surgery. The parotid gland lesion decreased after 1 month of oral administration of sorafenib, and increased again after 2 months of the targeted drugs.After the disease progressed, apatinib was switched to targeted therapy, and the disease progressed again after 5 months under control.Overall survival is nearly 15 months.We report an additional case of the rare metastasis of hepatocellular carcinoma to the parotid glands. Furthermore, the present case demonstrates the importance of pathological diagnosis and general systemic examination for obtaining an accurate nal diagnosis.


Background
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, with about 841,000 diagnoses and 782,000 deaths per year [1]. it is estimated to be responsible for 746,000 deaths per year (9% of the total deaths from cancer) [2].The most common risk factor for HCC is chronic HBV infection, which accounts for more than 50% of all cases globally and 60-80% in some Asian countries such as China, Korea, and Vietnam [3].HCV, HBV, can directly lead to HCC without the presence of cirrhosis.Some patients with liver cancer have alcoholic hepatitis or a history of heavy drinking [4][5][6][7].Alpha-fetoprotein (AFP) is the most frequent used serological marker,AFP is an important index for the diagnosis of primary liver cancer. Elevated AFP level can be used as the basis for the clinical diagnosis of liver cancer,but some patients with liver cancer have normal AFP [8].in addition to AFP, histopathological biopsy is the gold standard for the diagnosis of liver cancer [9].The common sites of liver cancer metastasis include intrahepatic metastasis, lung, peritoneum, bone, adrenal gland, etc. The prognosis for liver cancer is very poor,Patients with metastases have worse prognosis.Liver cancer rarely metastases to other than common sites like the salivary glands. Metastasis to rare sites of liver cancer is easily to be ignored.This paper reports a case of parotid gland metastasis of hepatocellular carcinoma.This patient was rst treated for facial mass and parotid gland enlargement,The patient complained that he had no history of hepatitis, the examination after admission indicated hepatitis B, with a history of small amount of alcohol consumption, and a slight increase in AFP. It was di cult to consider the diagnosis of liver cancer in this case, but the parotid lesion was excised and pathologically con rmed as metastatic liver cancer.Parotid gland tumors can be classi ed as benign and malignant, and malignant tumors can be divided as primary or metastatic. The primary foci of metastatic parotid gland carcinoma are mostly from the head and neck, the liver of metastatic carcinoma in the parotid gland origin is very rare, and easy to be ignored, thus increasing the di culty of diagnosis and treatment and easily delaying the treatment of patients.especially when the AFP is normal or no history of hepatitis, patients are less likely to consider the transfer of liver cancer.histopathologic diagnosis is particularly important in the diagnosis of the tumor, including excision biopsy, biopsy.So far, a total of only 7 English literatures have reported parotid gland metastasis of liver cancer, which further suggested the particularity of this situation [10][11][12][13][14][15][16]. We here report an additional case of this rare association.

Case Report
A 52-year-old male presented with a progressively enlarging no painful right facial swelling for 1 months.
Physical examination revealed right-sided swelling in the face of about 5×5cm on the parotid gland that was rm.and later pain appeared,After the use of amoxicillin and other anti-in ammatory drugs, the pain was relieved, but the tumor gradually increased, accompanied by increased pain, with numbness and discomfort of the right lip. He also reported a history of signi cant weight loss and progressive abdominal distention and discomfort.No family history of cancer.The previous history of hepatitis b was unknown, and the patient was diagnosed as hepatitis b during the rst diagnosis and hospitalization,No signs of cirrhosis.After diagnosis, patients were regularly treated with entecavir orally.With a drinking history of 35 years, 100ml per day.AFP 59.26ng/ml (normal range0-7ng/ml During the course of the disease, the highest value of AFP is 132.8ng/ml, CA125 CA199 CA724 CEA are all normal.computed tomography (CT) scan revealed As shown in gure a :Soft tissue shadows were observed in the deep part of the right parotid gland, with a size of about 59mm*57mm*45mm. The enhancement scan showed obvious uneven enhancement. Destruction shadows were observed in the adjacent bone, the peripharyngeal wall was thickened and the pharyngeal space was narrowed, and no obvious enlarged lymph nodes were observed in the neck.Multiple nodules in both lungs were considered as metastatic tumors.Multiple mediastinal lymph nodes were enlarged, metastasis was considered, and the right lobe of the liver was occupied.Right adrenal nodule, metastatic possibility.The right deep maxillofacial neck mass was cut and biopsied. During the surgery, it was found that As shown in gure b : the tumor was located in the deep lobe of the right parotid gland and the deep muscle of the right masseter, with complete envelopment, white content, loose tissue, crispy sh-like tissue, and abundant blood supply.Pathological diagnosis: right facial malignant tumor, which was consistent with hepatocellular carcinoma metastasis in combination with HE morphology and immunohistochemistry. The size was CT indicated that soft tissue shadow was seen in the deep part of right parotid gland, with the size of about 59mm*57mm*45mm.The patient was then given targeted therapy orally with sorafenib.The parotid gland lesion was signi cantly reduced after one month, e cacy evaluation is Partial response(PR). The lesion developed again after continued oral administration of sorafenib for 2 months, e cacy evaluation is progressive disease(PD).and replacement of apatinib targeted therapy were given.
The disease progressed again after 5 months of oral administration of apatinib, The patient was treated with traditional Chinese medicine and died six months later.

Conclusions
This paper reports a case report of a male patient with IV-stage hepatocellular carcinoma (stage D according to Barcelona Clinic of Liver Cancer, BCLC, staging classi cation) with right parotid gland metastasis, complicated with lung metastasis, Multiple mediastinal lymph nodes and the right lobe of the liver,Right adrenal nodule metastasis.which is the rst case reported in China.The patient was treated for parotid gland enlargement, and the pathological diagnosis was made by parotid gland tissue resection and pathological biopsy.Ki67 (about + 70%),AFP is slight increase, the patient was diagnosed hepatitis B for the rst time during the rst diagnosis and hospitalization.The tumor recurred in the postoperative site of parotid gland 22 days after surgery. The parotid gland lesion decreased after 1 month of oral administration of sorafenib, and increased again after 2 months of the targeted drugs.After the disease progressed, apatinib was switched to targeted therapy, and the disease progressed again after 5 months under control.Overall survival is nearly 15 months.We report an additional case of the rare metastasis of hepatocellular carcinoma to the parotid glands. Furthermore, the present case demonstrates the importance of pathological diagnosis and general systemic examination for obtaining an accurate nal diagnosis.

Discussion
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide [17].Despite advances in its treatment, liver cancer remains one of the most di cult cancers to treat. For patients with early HCC, local ablation, surgical resection or liver transplantation provide curative potential. However, recurrence of HCC remains a major problem after curative treatment.Treatment of advanced hepatocellular carcinoma (HCC) remains a challenge. Although several antiangiogenic targeted agents and checkpoint inhibitors have been recently approved for the treatment of HCC, the objective tumor response rates of these agents are in the range of 10% to 24% [17,18].In view of the limited therapeutic effect of liver cancer, early detection and diagnosis and treatment of liver cancer patients are of great importance.Since parotid gland metastasis of hepatocellular carcinoma is very rare, it is already at an advanced stage at the time of diagnosis. If there is a missed or misdiagnosed situation that cannot be detected in time, and the patient cannot receive timely and effective treatment, the overall survival and prognosis of the patient will be worse. This report and the past Relevant case reports suggest the existence of this phenomenon, which has resulted in earlier diagnosis and treatment for patients, which has brought bene ts for patient.
Several meta-analyses have demonstrated that the risk of HCC is 15-20 times greater among HBVinfected individuals compared with the uninfected population [19]. with increasing awareness of reporting and better screening services,China have reported increasing incidence of HCC for males and females [20]. Despite the high incidence of liver cancer throughout China, a decreasing trend has been observed in some regions because of neonatal vaccination for HBV infection [20].Effective and potentially long-term antiviral therapy should be started in all patients with chronic hepatitis B infection and active liver disease.The use of hepatitis B vaccine and antiviral treatment can better prevent and control the occurrence and development of liver cancer.The case of this article found hepatitis B when the liver cancer was diagnosed, at this time there were distant metastases. The stage was advanced and the prognosis was poor.Unfortunately, the patient had not been examined for hepatitis B before, and had no prior antiviral treatment,which also reminds us of the importance of physical examination and early prevention. For hepatitis patients, we need to be more alert to the occurrence of liver cancer.
Hepatocellular carcinoma (HCC) commonly metastasizes to the lungs, lymph nodes, peritoneum, adrenal glands, and bone, although there are uncommon reports of metastases to the ovaries, skin, heart, pharynx, orbit, and external auditory canal [21--26]. Metastasis to parotid glands is rare and to the best of our knowledge only 7 cases of hepatocellular carcinoma metastatic to parotid glands have been reported since 1998 [10][11][12][13][14][15][16], suggesting that this association is rare.If the patient has a history of liver cancer, parotid gland enlargement is more likely to indicate the possibility of liver cancer metastasis.but If the patient is rst diagnosed because of parotid gland enlargement,espicially when the patient with no history of hepatitis, alcoholic liver or liver cancer, and with normal or slightly elevated AFP, which made the diagnosis of liver cancer more di cult and easy to be misdiagnosed, It is easy to cause misdiagnosis and missed diagnosis when the diagnosis of HCC was not clinically suspected,because there are no highrisk factors for liver cancer.Especially, The primary site of parotid gland metastasis is mostly located in the head and neck region,metastatic localizations from liver cancer are even more rare. which should arouse the vigilance of the medical staff.
Although CT, Magnetic Resonance Imaging(MRI), ultrasound and other examinations play an important role in diagnosing the nature of parotid gland masses and tumor staging, and have guiding signi cance for treatment after diagnosis, the diagnosis of histopathology is still very important,oncologists often use pathological diagnosis to determine the nature and type of the tumor.Biopsy for parotid gland tumors include ne needle aspiration biopsy and parotidectomy.There are reports that ne needle aspiration biopsy of parotid gland in the diagnosis of malignancy with the sensitivity of 54-92%, adn speci city in the range of 86-100%.there are false-negative and the false-positive [27,28].Excision biopsy of parotid gland is the other method of diagnosis. It cannot be used for treatment of patients with liver metastases. However, because tissue samples are more abundant than ne needle biopsy, it is more helpful for accurate pathological diagnosis.In this case, the pathology was con rmed by parotidectomy biopsy,After the parotid gland tumor was removed, the patient's parotid gland recurred quickly.
As the prognosis of HCC depends largely on the stage at which the tumor is detected, detection of HCC early in its development is critical to improve the survival of affected patients [29]. The treatment of patients with advanced liver cancer is very important.Sorafenib and lenvatinib were the target therapy that improved overall survival (OS) for unresectable HCC (uHCC) [30][31][32]. For patients who progress after failure of rst-line treatment,subsequent systemic anticancer medication could be an important treatment that may lead to longer OS.Apatinib is a novel receptor tyrosine kinase inhibitor selectively targeting VEGFR-2. It is an orally-bioavailable agent currently being studied in several solid tumour types [33].In addition to the targeted therapy,A number of ongoing clinical trials related checkpoint inhibitors aiming to improve the therapeutic effect of liver cancer patients [34].The rst-line treatment of this patient is sorafenib,progressed after 2 months of the targeted drugs.After switching to apatinib, the condition was controlled for 5 months, and then the condition progressed again.Later, the patient chose traditional Chinese medicine for treatment,died six months later.
The treatment effect of advanced liver cancer is limited, and the overall survival time is short. Most patients have a history of hepatitis, without systemic antiviral treatment, and some patients with normal AFP level or Slightly elevated AFP level, which is easy to be ignored. When liver cancer is diagnosed, it is already in the advanced stage, resulting in low overall treatment e ciency. This case report is very meaningful. 1. Hepatitis B was found in the patient's rst visit. He has an unknown history of hepatitis. However, it is not ruled out that the patient has hepatitis in the past but is unknown and has not been diagnosed and treated. 2. The patient's rst visit to the Department of Oral Surgery, AFP level is not signi cantly increased,the rst physician did not consider the possibility of Parotid gland metastasis of liver cancer, and performed local resection based on the primary tumor of the parotid gland, and did not give timely treatment for liver cancer after the operation. After the tumor recurred at the parotidectomy site, the patient was transferred to the oncology department for liver cancer related treatment. More than 20 days after the postoperative pathological diagnosis of this patient, systemic anti-tumor therapy for liver cancer was started. 3. Oncologists perform treatment according to the diagnosis of histopathology, suggesting the importance of pathological diagnosis in tumor diagnosis. This case suggests that our clinicians have insu cient knowledge about the metastasis of rare parts of liver cancer, such as parotid gland metastasis,which easily delays the diagnosis and treatment of patients. This case is the eighth reported case of metastatic hepatocellular carcinoma to the parotid gland. It is hoped that more and more reports of rare cases can attract the attention of clinicians. For early prevention, early detection and treatment of patients provide more help.