Journal of Cranio-Maxillo-Facial Surgery 42 (2014) 1997e2001

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Case report

Metastasis to the jaws as a first manifestation of hepatocellular carcinoma: Report of a case and analysis of 41 cases Michael Pesis*, 1, 2, Shlomo Taicher a, b, Gahl Greenberg c, Avraham Hirshberg d a

Department of Oral and Maxillofacial Surgery, The Maurice and Gabriela Goldschleger School of Dental Medicine, Tel Aviv University, Tel Aviv, Israel Department of Oral and Maxillofacial Surgery, Chaim Sheba Medical Center, Tel Hashomer, Israel c Neuroradiology Unit, Department of Diagnostic Imaging, Chaim Sheba Medical Center, Tel Hashomer, Israel d Department of Oral Pathology and Oral Medicine, The Maurice and Gabriela Goldschleger School of Dental Medicine, Tel Aviv University, Tel Aviv, Israel b

a r t i c l e i n f o

a b s t r a c t

Article history: Paper received 15 March 2014 Accepted 3 September 2014 Available online 19 September 2014

Introduction: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Local metastasis is common but metastasis to the jaw is rare with 40 reported cases in the English language literature. Report of case: We describe a case of a 54-year-old man who, for the past two months, had noticed a rapidly growing facial mass in the posterior mandibular area. The patient was known to be a hepatitis C virus carrier and suffered from liver cirrhosis but the presence of HCC was unknown. Methods and results: The English language literature was searched for documented cases of HCC metastasis to the jaw, applicable data was evaluated. The literature analysis revealed 41 reported cases (including the present case). In most cases (81%) the jaw lesion was the only known metastasis at the time of HCC diagnosis. Clinical presentation occurred up to 2 years before discovery of the jaw metastasis. Patients with HCC jaw metastasis have a poor survival rate with an average of 6.1 months between diagnosis and death. Conclusions: This study shows that an isolated jaw mass may be the initial presentation of HCC and therefore must be considered in the differential diagnosis, especially in the presence of known liver cirrhosis or chronic viral hepatitis. © 2014 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

Keywords: Mandibular metastasis Oral metastasis Hepatocellular carcinoma Jaw bone metastasis

1. Introduction Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide (Mittal and El-Serag, 2013). Over 30,000 new cases are diagnosed annually in the USA, with over 21,000 deaths in 2013. Chronic hepatitis B (HBV) and C (HCV) are recognized as the major risk factors of HCC, with the risk being greater in the presence of coinfection with both viruses (Benvegnù et al., 1994; Ikeda et al., 1993; Chiaramonte et al., 1999). Most HCC metastases are local, in the liver, but extrahepatic metastases are also common. HCC metastases to the jaw are very rare with approximately 40 cases reported in English language publications. Consequently their differential diagnosis is quite difficult. We present a new case of HCC metastasis to the mandible and review the literature aiming to * Corresponding author. Tel.: þ972 544314364; fax: þ972 774002436. E-mail address: [email protected] (M. Pesis). 1 As partial requirements for DMD thesis, The Maurice and Gabriela Goldschleger School of Dental Medicine, Tel Aviv University. 2 In memory of my beloved father, Leonid Pesis, 1949e2004.

compare the present case with those previously reported, and report key features which should raise suspicion of HCC metastasis to the jaw. 2. Report of case A 54-year-old man was referred to the department of oral and maxillofacial surgery in August 2003 for evaluation of a left, rapidly growing facial mass in the posterior mandible that had been noticed for two months. The swelling was accompanied by numbness of left lower lip and cheek and gingival bleeding. The patient also suffered from bleeding gums and loss of teeth for a couple of years before his admission and was treated by his dentist for what was thought to be periodontal disease. The patient's medical history revealed liver cirrhosis due to HCV infection. Physical examination disclosed a well-nourished man in no acute distress. Facial fullness in the left posterior mandibular region including the body, angle and the ascending ramus, was notable, with decreased touch sensation and a nociceptive response in the

http://dx.doi.org/10.1016/j.jcms.2014.09.005 1010-5182/© 2014 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

1998

M. Pesis et al. / Journal of Cranio-Maxillo-Facial Surgery 42 (2014) 1997e2001

left cranial nerve V3 distribution. Intraoral examination showed a submucosal mass associated with the left mandible and palpable in the medial and lateral aspects. Blood tests revealed alpha-fetoprotein (AFP) levels in the normal range (26.4 ng/ml). Due to the risk of bleeding complications, fine-needle aspiration (FNA) was used and revealed cells in groups and clumps consistent with a malignant neoplastic process from unknown origin. A panoramic radiograph (Fig. 1) displayed a mostly defined radiolucent lesion and a pathological fracture of the lower left mandibular body. Computed tomography as well as magnetic resonance imaging demonstrated a large destructive mass in the left mandibular area (Figs. 2, 3A and 3B). Under local anesthesia a biopsy was performed; significant bleeding from the mass was encountered during the operation. Histopathology (Fig. 4) showed malignant cells with bright, oxyphilic cells forming trabeculae and small solid surfaces separated by vascular stroma imitating sinusoids. The tumor cell nuclei were large with prominent micronuclei and mild to moderate pleomorphism; abundant cytoplasm with clear borders between the cells. Few mitoses were notable, no necrosis was seen. Immunochemical staining revealed variable positivity for PAS, CK18, HEP and EMA but was negative for iron, CK19, CK7, CK20, S100, AFP, CD10 and Vim. CEA produced intense staining in a canalicular-membranous pattern. The proliferative index with Ki67 staining was 12%. Pathologic diagnosis was most consistent with metastatic HCC. The patient was referred to the oncology department for further evaluation and initiation of treatment. A hepatic mass was discovered by radiological tests in the oncology department and a total dose of 3000 cGy was delivered to the mandibular mass. Chemoembolization therapy with Embospheres and cisplatin was administered for the mandibular and the hepatic masses. The patient's condition deteriorated despite the intensive treatment, with further enlargement of the mandibular lesion accompanied by recurrent events of massive bleeding; external carotid artery ligation was performed in an attempt to stop the bleeding. Disseminated tumor masses were found in a total body scan and the AFP levels gradually rose to a level of 359 ng/ml. The patient died at his home 15 months after the initial diagnosis, he was 55-year-old. 3. Literature review and discussion A total of 41 cases of metastatic hepatocellular carcinoma (MHCC) involving the jaw were analyzed, these were drawn from the English language literature published between 1940 and 2013 (with the addition of the present case). Relevant data was depicted and shown in Tables 1 and 2. The present analysis revealed 41

Fig. 1. Panoramic radiograph displaying a mostly defined radiolucent lesion approximately 4 cm in size, with a missing bone segment and a pathological fracture at the lower left mandibular body, the lesion wraps around the mandibular body and ascending ramus.

Fig. 2. Computed tomography showing a large radiolucent mass in the left mandibular area measuring 4.5  4.5  2 cm with well-defined borders and containing calcification; marked bony destruction present.

reported cases (including the present case) of which 35 were male and 6 were female; this corresponds with the male predominance of HCC (Lui et al., 2000). Patient age ranged from 15 to 82 years (mean 61, median 62); similar to the mean age of all head and neck metastases (Thiele et al., 2011). Timing of the appearance of the metastasis was reported in 36 cases, and in 26 of these (72%) the discovery of the metastasis was before the HCC was diagnosed, within a range of 0.5 to 12 months (mean 3, median 2). In 29 cases out of the total of 41 (71%) the jaw metastasis was the first metastasis. The mandible was the most common site of MHCC (37cases, 90%), mainly in the posterior area. Only in two cases (5%) it was located in the maxilla and in two cases (5%) metastases occurred in both jaws. The clinical presentation of MHCC to the jaw was reported in all cases with swelling being the most common sign (29 cases, 71%); followed by numbness (19 cases, 46%); pain (16 cases, 39%); bleeding (12 cases, 29%); proliferative mass (11 cases, 27%); loss of teeth (8 cases, 20%); ulceration (5 cases, 12%); and trismus (2 cases, 5%). The symptoms appeared between 0.25 and 24 months (mean 3.4, median 1) before the metastasis was diagnosed (reported in 31 cases). The size of the lesion was reported in 22 cases, ranging from 0.2 to 9 cm (mean 3.95, median 3.25). The radiographic presentation of the MHCC lesions to the jaw, in most of the cases, was an illdefined radiolucency. Medical history concerning past liver conditions was reported in 25 cases, of which 17 (68%) had hepatic cirrhosis; 11 (44%) were alcoholics; and HCV and HBV positivity was reported in 11 cases (44%) and 3 cases (12%) respectively. AFP levels were reported in 24 cases, in 16 of these (67%) the levels ranged from 114 to 67, 800 ng/ml, higher than the normal range (>50 ng/ml). Treatment was mentioned in 27 cases with surgery being the most popular choice (14 cases, 52%), followed by radiation (11 cases, 41%) and chemotherapy (8 cases, 30%); a combination of chemotherapy and radiation was performed in five cases (18%), and surgery and chemotherapy was performed in one case (4%). Since Dick first reported a case of HCC metastasis to the mandible in 1957, 40 cases have been documented. HCC is the most

M. Pesis et al. / Journal of Cranio-Maxillo-Facial Surgery 42 (2014) 1997e2001

1999

Fig. 3. (A and B) Axial T1 post-contrast image and a corresponding T2 weighted image at the level of the mandible both depict a large, expansive and heterogeneous mass occupying the left masticator space. The tumor mass appears to emanate from the body and ramus of the left mandible causing destruction of both buccal and lingual cortices with greater lateral extension.

Fig. 4. (A and B) Photomicrograph of the biopsy specimen from the jaw: A) Low power view demonstrating sheets of solid tumor cells adjacent to a trabecula of bone (hematoxylin and eosin stain; magnification, 40); B) High power photomicrograph showing polygonal epithelioid cells with abundant eosinophilic cytoplasm resembling hepatocytes. The tumor cells exhibit nuclear pleomorphism, prominent nucleoli, and mitotic figures (hematoxylin and eosin stain; magnification, 400).

common malignancy of the liver with the highest incidence occurring in East Asian populations (Anthony, 2001; Cuardo et al., 2007). HCC usually undergoes intrahepatic metastasis in the early stages, and only 25% of HCC patients develop extrahepatic metastases (Natsuizaka et al., 2005). Metastasis of HCC to the jaw is very rare. When it does occur, the most frequently affected site is the mandible (Teshigawara et al., 2006). It has been suggested that the mandible is the most common site because it contains hematopoietic tissue (Ashar et al., 1997). The diagnosis of HCC metastasis to the jaw can be challenging, especially when the primary tumor has not yet been discovered. Several pathways of HCC metastasis to the jaw have been proposed. One of them is the hematogenous pathway; 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 (Takinami et al., 1995). Tumor cells may reach the mandible through the paravertebral veins bypassing the pulmonary, inferior caval and portal venous circulations (Batson, 1940). 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 (Hirshberg et al., 2008) as appeared in 40 of 41 cases in study. Affected patients typically present with a slow growing swelling within the jaw with associated numbness, pain and

bleeding. A proliferative mass, loss of teeth and ulceration may also occur. The classic presentation of a patient with jaw metastasis may lead to the presumptive diagnosis of a metastatic lesion; a medical history of liver cirrhosis along with high levels of AFP can point toward a primary tumor in the liver. Although high levels of AFP may be a clue to the diagnosis, it may be also in the normal range. In the present case, the patient received a combination of local radiation therapy to the oral lesion and chemotherapy for the primary and the metastatic lesions. In view of the high vascularity of metastatic HCC tumors and the coagulopathy that often accompanies primary liver disease, a resection or even a biopsy can be complicated by hemorrhage. In rare cases, hemorrhage can be so severe that extensive procedures, such as external carotid artery ligation or embolization, are necessary. Because of the severity of this complication, some authors suggest that if metastatic HCC in the jaw is suspected, an FNA biopsy should be performed to confirm the diagnosis due to its usefulness for evaluation of metastatic disease in oral and maxillofacial region, with sensitivities ranging from 77 to 100% and 100% specificity (Barnard et al., 1993; Singh et al., 2011); only if the aspiration biopsy cannot confirm the diagnosis, should an open biopsy be performed (Barrera-Franco et al., 1993). Patients with HCC with bone metastasis have a very poor survival rate; 1-year survival is 15%e20%, and 2-year survival is only 4%

2000

M. Pesis et al. / Journal of Cranio-Maxillo-Facial Surgery 42 (2014) 1997e2001

Table 1 Summary of publicationsa. Case number

Author (Year reported)

Gender

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40

Dick et al. (1957) Appenzeller et al. (1971) Yacabucci et al. (1972) Muldoon (1974) Goveia and Bahn (1978) Vigneul et al. (1982) Tung Ma et al. (1985) Horie et al. (1985) Horie et al. (1985) Mucitelli et al. (1988) Marker and Clausen (1991) Doval et al. (1992) Barrera-Franco et al. (1993) Takinami et al. (1995) Yoshimura et al. (1997) Ashar et al. (1997) Lalikos et al. (1992) Chin et al. (1998) Afroze et al. (1998) Papa et al. (2001) Pires et al. (2004) Junquera et al. (2004) Chen et al. (2005) Kim and Kim (2005) Teshigawara et al. (2006) Huang et al. (2007) Tamiolakis et al. (2007) Han et al. (2007) Li et al. (2008) Enokiya et al. (2008) Kamatani et al. (2008) Magliocca et al. (2009) Shen et al. (2009) Shen et al. (2009) Shen et al. (2009) Shen et al. (2009) Bair et al. (2010) Fujihara et al. (2010) Lasiter et al. (2011) Yu et al. (2012)

M M M M M M M M M M M M M M M M F M M M M M M M M F M M M F M F M F F M M M M M

4. Conclusions This report describes a new case of HCC metastasis to the mandible and a literature review. Metastatic HCC to the jaw is very rare; however, it must be considered by clinicians in the differential diagnosis of patients who presents with a rapidly growing jaw mass, especially in patients with known liver cirrhosis or chronic viral hepatitis. Despite advanced medicine, patients with a diagnosis of MHCC to the jaw carry a grave prognosis. Conflict of interest statement All authors certify that there are no financial and/or personal relationships with other people or organizations that could inappropriately influence (bias) our work. Acknowledgments The authors would like to thank Professor Shlomo Calderon from the Department of Oral and Maxillofacial Surgery and Professor Amos Buchner from the Department of Oral Pathology and Oral Medicine, The Maurice and Gabriela Goldschleger School of Dental Medicine, Tel Aviv University, Israel for their assistance. The authors would like to thank Mrs, Yulia Kirichansky for her technical assistance. References

M- Male, F- Female. a This table does not include the present case.

Table 2 Summary of data analysis. Clinical data Mean age, years (range) Time to discovery of metastases (months) Size of lesion (cm) Time to death (years)

61 (15e81) 0.5e12 (mean 3) 0.2e9 (mean 3.95) 0.33e17 (median 5)

Site

Mandible Maxilla Both jaws Swelling Numbness Pain Bleeding Proliferative mass Loss of teeth Ulceration Trismus Hepatic cirrhosis Alcoholism HCV HBV Surgery Radiation Chemotherapy Chemotherapy + radiation Surgery + chemotherapy

Clinical presentation

Medical history

Treatment

HBV: hepatitis B virus; HCV: hepatitis C virus.

(Kaizu et al., 1998). In our study we found a mean period of 12.4 months survival time after the discovery of HCC, and a mean period of 6.1 months survival time after discovering the jaw metastasis.

% 90 5 5 71 46 39 29 27 20 12 5 68 44 44 12 52 41 30 18 4

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