Dimitrios Giakoustidis, Athanasios Apostolos Gargavanis, Nikolaos Salveridis, Evangelos Cholongitas,Emmanouil Sinakos, Konstantinos Papapolychroniadis, Vassilios Papanikolaou

1Division of Transplant Surgery, Department of Surgery, Medical School, Aristotle University of Thessaloniki, Hippokration General Hospital, 54642 Thessaloniki, Greece.

2The 4th Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippokration General Hospital, 54642 Thessaloniki, Greece.

Total regression of hepatocellular carcinoma bone metastases, after liver transplantation,with sorafenib-everolimus

Dimitrios Giakoustidis1, Athanasios Apostolos Gargavanis1, Nikolaos Salveridis1, Evangelos Cholongitas2,Emmanouil Sinakos2, Konstantinos Papapolychroniadis1, Vassilios Papanikolaou1

1Division of Transplant Surgery, Department of Surgery, Medical School, Aristotle University of Thessaloniki, Hippokration General Hospital, 54642 Thessaloniki, Greece.

2The 4th Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippokration General Hospital, 54642 Thessaloniki, Greece.

Article history:

Liver transplantation,

hepatocellular carcinoma,

bone metastases,

sorafenib,

everolimus

Hepatocellular carcinoma (HCC) represents the 5th commonest malignancy worldwide. Liver transplantation consist a radical and most ef ficient treatment for HCC. Tumor recurrence or metastases after liver transplantation is not uncommon. Hereby is presented a case of a patient transplanted for alcoholic liver disease and HCC and presented with bone metastases a few months later. Treatment with sorafenib and everolimus showed full regression of the metastases. In conclusion, the point of this report is to advertise a single case of total regression of bone lesions due to HCC recurrence, with the combination of mammalian target of rapamycin and sorafenib, along with radiation.

INTRODUCTION

Hepatocellular carcinoma (HCC) consists a healthcare problem with rising incidence rates.[1]Liver transplantation (LT) is a radical treatment for HCC. In order a patient with HCC to receive a liver graft, he must ful fill certain enlisting criteria[2]and no extrahepatic disease. Tumor recurrence or metastases after liver transplantation for HCC is not uncommon. Sorafenib has been used as rescue therapy in patients with recurrent HCC after LT.[3]We hereby present a case of a patient transplanted for alcoholic liver disease(ALD) and HCC that presented with bone metastases a few months later. He was treated with sorafenib and everolimus, showed full regression of the metastases and he is still alive 9 years after LT.

CASE REPORT

A 63-year-old male patient was enlisted for LT forliver cirrhosis due to ALD. He was presenting portal hypertension, ascites and episodes of encephalopathy.His model for end-stage liver disease (MELD)score was 21. He was transplanted with piggy-back technique, from a heart-beating donor. Cold ischemia time was 9 h. He was put on triple immunosuppression maintenance therapy with prednizolone, mycophenate mofetil and cyclosporine.

The explant’s pathology report revealed the presence of two incidental HCC lesions measuring 15 and 20 mm,with no portal involvement, of medium differentiation,with pseudocapsule, clear-cell type, without extrahepatic nodules or other findings. The post-operative course was uneventful. His immunosuppression therapy was changed to tacrolimus and everolimus, along with tapering of prednizolone. Tacrolimus and everolimus levels were monitored.

Two months post transplantation the patient complained of back pain. Bone Scanning 99m Technetium helix destabilizing protein (99mTc-HDP) revealed 2 osteoblastic lesions on the T8 and T11, possibly secondary-HCC lesions. Prednizolone was ceased and sorafenib 400 mg bid was initiated, along with ibandronic acid (diphosphonic acid) qd. Radiotherapy was induced,photons 60Co. He received a total of 2,300 centigray(cGy), in doses of 46 cGy, 5 times/week.

Otherwise the patient was in good condition. His kidney function with radioisotope renography with 99m Technetium diethylene triamine pentoacetic acid (99mTc-DTPA) was 52 mL/min/1.73 m2. Alpha fetoprotein (AFP) level was 6.6 ng/mL.

Seven months after the first discovery of the spinal osteoblastic lesions, the repetition of the 99mTc-HDP,revealed further progress of the disease [Figure 1].New lesions were being detected at the 5th, 6th, 7th,and 8th left ribs. Magnetic resonance imaging (MRI)scan failed to reveal any additional findings. Therapy remained the same.

从以上分析可以看出：虽然主要家具大国的进出口量数额庞大，但大部分国际木质家具贸易是在已划分好的世界经济区域内进行，并且在经济区域内的贸易额达到世界木质家具贸易额的一半。其中，欧洲区域内的家具贸易现象尤为突出，其经济圈内的贸易额比例达到四分之三左右，而欧洲区域外的贸易额仅占四分之一;在北美自由贸易区，由于美国和加拿大都是家具进口大国，所以其区域外的家具贸易占比也高达四分之三左右;而在亚太地区，众多国家的家具市场十分发达，且以出口为主，所以仅有约40%的家具发生在亚太经济圈内。

Another 99mTc-HDP bone scanning 18 months post LT showed, for the first time, regression of the rib lesions,while the known 2 spinal lesions were signi ficantly minimized. Therapy remained unaltered. Patient’s clinical condition was excellent.

Finally, 28 months post LT, a new bone scanning certi fied the complete regression of all the osteolytic lesions[Figure 2].

DISCUSSION

HCC is the third cause of cancer related mortality nowadays, according to World Health Organization(WHO). The primary etiologic factor is liver cirrhosis.To the present case, HCC was incidental finding in the explant. A prior transplantation computed tomography (CT) failed to detect the presence of liver or extrahepatic lesions. Additionally, AFP levels were low [Table 1], failing to justify a position emission tomography (PET) scan preoperatively. Even if the patient was evaluated for Milan Criteria (MC),according to the explants’ pathology, the patient would be inside MC. Moreover, piggy-back technique is the standard LT procedure performed by our center, like many other centers universally. It does not consisting a risk factor for HCC recurrence, compared to the classic technique.

Figure 1: Initial 99m Technetium helix destabilizing protein scintigraphy showing metastatic lesions in the spine and ribs. POST:posterior; ANT: anterior; LAO: left anterior oblique

Figure 2: 99m Technetium helix destabilizing protein scintigraphy post sorafenib, immunosuppresion modi fication and radiation, showing regression of metastatic lesions in the spine and ribs. POST: posterior; ANT: anterior; LAO: left anterior oblique

The induction of sorafenib, an oral multi-kinase inhibitor, targeting HCC control, demands compensated liver function, and applies to patients with advanced HCC.[4]Regarding HCC recurrence post LT, the current strategy remains controversial. Recurrence can be located to liver graft, lung, bone, abdominal lymph nodes, adrenal glands and peritoneum. According to De Angelis et al.,[5]on a total of 61 studies selected,the median time recurrence presented was 13 months post transplantation, while 67% of patients presented with extra-hepatic lesions.[5]Overall survival was 12.97 months.

A classi fication of management according to the location of the recurrence has been attempted,recently. Toso et al.[6]when HCC reappear, underline the importance of immunosuppresion change to mTOR and propose initiation of sorafenib only for nonresectable multiple lesions, or cases that cannot pro fit of less invasive strategies, like radio frequency ablation or transarterial chemo embolization. If the recurrence is limited in the liver, without extrahepatic spread,local excision should be attempted.[7]The initiation of sorafenib finds place in cases of advanced HCC, when no other approach is plausible.This plan though, is not free of complications.Discontinuation of the sorafenib treatment due to adverse side effects is not uncommon.[8]The induction of radiation as an only and palliative treatment, is not improving the survival rates. In the study of Seong et al.,[9]51 patients received radiation therapy for 77 osteolytic metastatic lesions. Though there was pain relief in 56 lesions (73%),1-year survival was only 15%. In the review of He et al.,[10]radiation therapy for bone lesions, due to HCC post LT,improves patients’ quality of life. It has the same impact for transplanted patients, as in non-transplanted.

Table 1: Patient data, before and after liver transplantation

Vanishing of osteolytic lesions, to a patient under treatment with sorafenib-mToR, after radiation, has not been reported so far, to our knowledge. Though no biopsy was being done, we are convinced on the malignancy: the pain and imaging spread was distinctive, and they disappeared after treated like bone recurrence.

The patient had an interesting natural history of the disease. HCC was an incidental finding of explants’pathology. Metastasis to the bones was an unexpected event, since tumors were small and AFP was low.Nevertheless the patient presented with spine and later with ribs metastases. Oncologically he was treated primary with sorafenib and secondary with mTOR drug inhibitor everolimus, along with radiation. His immunosuppression therapy was revised accordingly.Our patient discontinued sorafenib 4 years ago, due to coronary disease. He remains under mTOR treatement,without new HCC recurrence [Figure 3].

DECLARATIONS

Authors’ contributions

Figure 3: Recent 18-FDG-PET/CT (Volume rendering) showing no lesions in ribs or spine. FDG: fluorodeoxyglucose; PET: position emission tomography; CT: computed tomography

Patient consent

The patient has provided us an informed written consent, available upon request.

Ethics approval

An ethics approval is not necessary for a case report;the informed written consent is suf ficient.

Literature search: D. Giakoustidis, A.A. Gargavanis,N. Salveridis, E. Cholongitas, E. Sinakos, K.Papapolychroniadis, V. Papanikolaou

Data acquisition: D. Giakoustidis, A.A. Gargavanis, N.Salveridis, E. Cholongitas, E. Sinakos

Data interpretation: D. Giakoustidis, A.A. Gargavanis,N. Salveridis, E. Cholongitas, E. Sinakos, K.Papapolychroniadis, V. Papanikolaou

Manuscript preparation: D. Giakoustidis, A.A.Gargavanis, N. Salveridis, E. Cholongitas, E. Sinakos Manuscript editing: D. Giakoustidis

Manuscript review: K. Papapolychroniadis, V.Papanikolaou

Financial support and sponsorship

None.

Con flicts of interest

There are no con flicts of interest.

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26 Jun 2017

Dr. Dimitrios Giakoustidis, Department of Surgery, Medical School, Aristotle University of Thessaloniki, 54642 Thessaloniki,Greece. E-mail: dgiak@auth.gr

How to cite this article: Giakoustidis D, Gargavanis AA, Salveridis N, Cholongitas E, Sinakos E, Papapolychroniadis K, Papanikolaou V. Total regression of hepatocellular carcinoma bone metastases, after liver transplantation, with sorafenib-everolimus.Hepatoma Res2017;3:205-8.

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Accepted: 29 Aug 2017

Published: 20 Sep 2017