British Journal of Radiology (2008) 81, 143-150
© 2008 British Institute of Radiology
doi: 10.1259/bjr/81811976
Radiation therapy to non-iatrogenic subcutaneous metastasis in hepatocellular carcinoma: results of a case series
Y-J HUANG, MD
1
W-C TUNG, MD
2
H-C HSU, MD
1
C-Y WANG, MD
1
E-Y HUANG, MD
1 and
F-M FANG, MD, PhD
1
1 Department of Radiation Oncology, 2 Division of Hepato-Gastroenterology, Chang Gung Memorial Hospital – Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan
Correspondence: Yu-Jie Huang, Department of Radiation Oncology, Chang Gung Memorial Hospital, 123 Ta-Pei Road, Niao Sung Hsiang, Kaohsiung Hsien, 833, Taiwan. E-mail: yjhuang{at}adm.cgmh.org.tw
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Abstract
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Non-iatrogenic subcutaneous metastasis of hepatocellular carcinoma (HCC) is rare. The aim of this study was to determine the characteristics of such non-iatrogenic subcutaneous metastases and to review the results of radiation therapy. Patients with HCC who were referred for radiation therapy to a subcutaneous mass from 1 January 1998 to 31 December 2005 were reviewed. Iatrogenic cases were excluded. The patients' characteristics, the properties of the lesion, radiation treatment, treatment response, and survival were studied. 24 subcutaneous metastatic lesions in 21 patients were studied. The patients' mean age was 58.2 years. The average latency period for the occurrence of the metastases was 291 days. The scalp was the most frequent metastatic site. At least a partial response was achieved in 20 of 24 lesions (83.3%), with radiation doses ranging from 8 to 64 Gy. No severe sequelae were recorded. The overall 6-month survival was 43.4%. ECOG (Eastern Cooperative Oncology Group) performance status and radiation dose were statistically significant factors for local treatment response. Performance status was also an independent factor for survival. Radiation therapy of subcutaneous metastases of HCC can achieve satisfactory results, especially in patients with a good performance status.
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Introduction
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Hepatocellular carcinoma (HCC) is a cancer that is common worldwide, especially in areas with a high prevalence of chronic viral hepatitis [1]. Most HCC patients die of liver failure or internal bleeding without developing clinically apparent extrahepatic metastases, since HCC tends to metastasize late in its course. On autopsy, extrahepatic metastases were found in over half of the cases [2, 3]. The most frequent sites of metastases in HCC patients are the lungs, lymph nodes, adrenal glands and bones [4–6]. Subcutaneous metastases are relatively rare. The majority of subcutaneous metastases appear to originate from needle tracks or surgical wound contamination [7–12]. Iatrogenic subcutaneous metastasis is not the natural course of HCC, and prevention using careful procedures is important. Cases of non-iatrogenic subcutaneous metastasis in HCC have been reported [13–21]. With improvements in HCC treatment, subcutaneous metastasis may be more frequently found because of prolonged survival. Thus, the treatment strategy for such lesions needs to be established rationally. Unfortunately, there are only case reports in the literature.
The treatment of choice for subcutaneous metastasis in HCC has not yet been determined. Since these patients are usually considered terminal, the lesions are usually only observed and no treatment is given. However, surgical resection of the metastatic lesion has been performed in a few cases [8, 10, 14]. Similarly to local treatment, the radiation therapy was rarely applied. There has been one report of an iatrogenic subcutaneous metastatic lesion that was treated with adjuvant radiation therapy postoperatively; the patient remained recurrence free [8]. However, in certain patients, radiation therapy should be able to treat subcutaneous metastasis of HCC. In this study, we reviewed the HCC patients with non-iatrogenic subcutaneous metastases who were referred to our department for local radiation therapy in order to analyse the lesions' characteristics and the results of treatment.
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Methodology
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Patients with HCC who were referred to our department for radiation therapy of subcutaneous masses from 1 January 1998 to 31 December 2005 were enrolled in the study. Patients whose lesions were located in areas that corresponded to bone scan hot spots were excluded, since these lesions were probably bone metastases. Patients with a subcutaneous mass that was continuous with the primary liver tumour on CT were also excluded, as the mass was considered to be the result of direct invasion rather than metastasis. The location of the subcutaneous metastasis was compared with the incision sites of any procedures that had been performed as recorded in the medical chart. If the lesion was located in the same region as an incision site, then the case was excluded as an iatrogenic case. Data were gathered from the patients' records until the end of the study, which was 31 March 2006.
The date that HCC was diagnosed, the date of the discovery of the subcutaneous mass, the date of the last follow-up and the date of death were extracted from the charts to determine the latent period for metastasis and survival. The Eastern Cooperative Oncology Group (ECOG) performance status [22] and the Child–Pugh classification [23] were determined at the time of the diagnosis of the subcutaneous metastasis based on the patients' records. The liver tumour stage and coexisting metastatic lesions were reviewed to assess host factors. The liver tumour stage was evaluated according to the T and N classification of the American Joint Committee on Cancer (AJCC) staging system for HCC [24]. If present, the locations of metastases were recorded. If available, the 
-fetoprotein (AFP) level at the time that the subcutaneous mass was detected was noted. The location of each subcutaneous mass was mapped on a sketch of the human body to determine the distribution of the metastases. The greatest diameter on palpation as recorded in the chart was noted. The pathology report, when available, was reviewed to verify the diagnosis. The radiation dose and technique were reviewed. The treatment response was evaluated according to the response evaluation criteria in solid tumours (RECIST) [25]. In addition, any adverse effects in the irradiated field and on the whole body during and after radiation therapy were noted.
The Statistical Package for the Social Sciences (SPSS, Windows version 13.0) was used to analyse the data. The Mann–Whitney U-test was used to evaluate the treatment response by individual factors. The Kaplan–Meier method was used to determine survival. The log-rank test was used to test for differences in survival, and the Cox regression model was used to determine the independent factors for survival. A p-value <0.05 was considered statistically significant.
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Results
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There were 1489 patients with HCC referred for radiation therapy during the study period; 55 (3.69%) were referred for treatment of subcutaneous masses. 28 patients (1.88%) had iatrogenic subcutaneous masses, 3 patients (0.20%) had protrusions from bone metastases and 3 patients (0.20%) had lesions that extended directly from liver masses. Thus, there were 21 patients (1.41%) with 24 non-iatrogenic subcutaneous metastases enrolled in the study.
Patient characteristics
The patients' mean age at the time of first referral for radiation to the subcutaneous mass was 58.2 years. 19 patients (90.5%) were men. The ECOG performance status was Grade 1 in 9 (42.9%) patients, Grade 2 in 9 (42.9%) patients and Grade 3 in 3 (14.3%) patients. Based on the Child–Pugh classification, 13 patients (61.9%) were classified as A, and 8 patients (38.1%) were classified as B. With respect to liver tumour stage, 4 patients (19.0%) were stage T2N0 and 17 patients (81.0%) were stage T3N0. 14 patients (66.7%) had metastases other than subcutaneous lesions when they were referred. The most frequent coexisting metastatic site was bone (12 patients, 57.1%), followed by the lungs (3 patients, 14.3%).
Lesion properties
The average latency period for the 24 subcutaneous metastases was 291 days (range, 0–1223 days). The serum AFP levels at the time that the subcutaneous metastases were diagnosed were available for 17 lesions; the values ranged from 7.32–6798 ng ml–1. In three (14.3%) patients, the subcutaneous metastasis was the initial manifestation of HCC. Two patients (9.5%) had more than one subcutaneous metastatic lesion: one patient had a right chest wall lesion followed by scalp and left chest wall nodules 90 and 108 days later, respectively; the other patient presented with concomitant metastatic lesions on the back and right forearm. Overall, the most frequent site of subcutaneous metastasis was the scalp (n = 8, 33.3%); Figure 1
shows the body surface distribution of the subcutaneous metastases. The mean size of the metastatic lesions was 6.0 cm; the maximum size was 12 cm. All lesions appeared to be solid palpable masses that were located beneath the skin with a grossly intact surface. No ulcerations, no superficial vein engorgement, and no erythematous changes were noted. In 10 lesions, the patients complained of tenderness (41.7%); 2 of the tender lesions were 
6 cm in size. Pathology was available to confirm the diagnosis for eight lesions (33.3%).
Radiation techniques and treatment responses
Depending on the lesion depth and location, either photon or electron beam radiation was used for radiation therapy. The irradiation field was defined as having a margin of at least 2 cm beyond the palpable mass edge. 13 lesions (54.2%) were irradiated with a 9–18 MeV electron beam using a single portal technique. 11 lesions (45.8%) were treated by opposing fields with a 10–15 MV photon beam. The treatment schedule was fractionated with a fraction size from 1.5 to 3 Gy, five times per week. All subcutaneous masses received radiation therapy with doses ranging from 8–64 Gy. Two lesions did not receive radiation doses greater than 30 Gy owing to the patients' declining general health; in these two patients, the treatment response was unavailable. By the end of the study, 2 lesions (8.3%) had a complete response (CR), 18 lesions (75.0%) had a partial response (PR) and 2 lesions (8.3%) had stable disease (SD). Following radiation, tenderness subsided in all symptomatic lesions. The ECOG performance status and the radiation dose were statistically significant factors for treatment response with p-values of 0.023 and 0.021, respectively (Table 1). The trends of radiation dose–response, ECOG status–response scatter charts are illustrated on Figure 2.
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Table 1. Mann–Whitney test for treatment response of subcutaneous metastasis in patients with HCC by the various factors
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Figure 2. The charts for the trends of treatment response by the significant factors in the Mann–Whitney U-test. (a) ECOG performance status–treatment response scatter. (b) Radiation dose–treatment response scatter chart. CR, complete response; PR, partial response; SD, stable disease; NA, not available.
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Sequelae and causes of death
During and after radiation treatment, of the 24 irradiated fields, 8 fields (33.3%) with doses ranging from 8 to 40 Gy had no reaction; 8 fields (33.3%) with doses ranging from 36–55 Gy had erythematous changes; 4 fields (16.7%) with doses ranging from 50–60 Gy had dry desquamation; and 4 fields (16.7%) with doses ranging from 56–64 Gy had moist desquamation. There were no recorded radiation-induced systemic complications. Four patients (19.0%) were alive at the time of the last follow-up, and two patients (9.5%) were lost to follow-up. Causes of death included infectious diseases, including sepsis and pneumonia, in six patients (28.6%); massive blood loss from hepatoma rupture or upper gastrointestinal (UGI) bleeding in five patients (23.8%); and liver failure in four patients (19.0%).
There were two unusual cases who had oral submucosal metastasis. One patient had an abdominal wall mass followed by a buccal submucosal metastasis 92 days later, and the other had concomitant metastatic lesions on the back and right forearm followed by gingival metastasis 65 days later. The buccal submucosal metastasis caused death as a result of massive bleeding.
Survival
Following the initial diagnosis of subcutaneous metastasis, the overall 6-month survival was 43.4%, and the overall 1-year survival was 22.8%. The survival of patients with subcutaneous metastases was compared with the survival of the other 1468 patients with HCC referred for radiation therapy to our department; there was no statistically significant difference between these two groups (Figure 3). On the log-rank test for survival by individual factors (Table 2), ECOG performance status, liver tumour stage and radiation dose were statistically significant. On the Cox regression model using the statistically significant variables for treatment response and survival (Table 3), the only independent factor for survival was ECOG performance status (p = 0.006). Figure 4 shows the survival difference according to performance status.
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Figure 3. The survival curves for patients with subcutaneous metastasis and all of the others with hepatocellular carcinoma(HCC) to radiation therapy.
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Figure 4. The survival difference according to performance status in patients with hepatocellular carcinoma(HCC) and subcutaneous metastasis for radiation therapy.
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Discussion
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Although the metastatic lesions that we studied may have actually been located in the epidermis, dermis, subcutaneous tissue or even muscle tissue, they all appeared as a solid palpable mass located beneath the skin. Since Dorland's Illustrated Medical Dictionary defines subcutaneous as "beneath the skin", we could categorize such metastases as being subcutaneous metastases. Subcutaneous metastases secondary to internal organ tumours are uncommon. Lookingbill et al. [26] reported that skin metastases occurred in about 5% of patients with internal organ carcinoma. In Western countries, the most common origins of cutaneous metastases from internal malignancies were the lungs in men and the breasts in women, according to Brownstein and Helwig [27]. In Asian countries, the usual origins of skin metastases were the stomach in men and the breasts in women, according to Koya and Oka [28]. Damron and Heiner [29] reviewed the literature dealing with distant soft tissue metastases. He found that the lungs were the most common primary source. In contrast, the most frequent metastatic sites of HCC are the lungs, lymph nodes, adrenal glands and bones [4–6]. Subcutaneous metastases of HCC were mostly due to iatrogenic causes, such as those associated with needle tract implantation [7–12]; nevertheless, non-iatrogenic subcutaneous metastases have been reported [13–20]. The reason that non-iatrogenic subcutaneous metastases of HCC are rare is not known, though the poor prognosis of patients with HCC may be one of the reasons. In this study, the average latency period before a subcutaneous metastasis appeared was 291 days. Owing to the aggressive nature of HCC, patients usually do not survive long enough for a subcutaneous metastasis to occur. Another possible explanation is that HCC invades the systemic circulation less frequently than it invades the portal veins. Therefore, subcutaneous metastasis, which is the result of systemic haematogenous spread, is rare. In this study, we found that the most frequent site of subcutaneous metastasis was the scalp (33.3%). In addition, two cases developed oral cavity submucosal metastasis during follow-up. It is thought that HCC tends to metastasize to hypervascular tissues once the tumour cells have spread to a surface organ. However, although subcutaneous metastasis is unusual, it can be the initial presenting sign of HCC [17–20]. In three patients (14.3%) in this study, a subcutaneous mass was the first clue for the diagnosis; these masses were located on the chest wall and the scalp. It has been reported that a soft tissue metastasis may occur in patients with a painful soft tissue mass without a prior history of cancer [29]. Thus, in patients presenting with a subcutaneous mass, the differential diagnosis should include internal organ metastasis, especially in countries where HCC is common.
The characteristics of patients with subcutaneous metastases did not vary widely. No patients had an ECOG performance status that was worse than 3 and a Child–Pugh classification that was worse than B. Using the AJCC staging system, all of the enrolled patients had a stage T2N0 or T3N0 liver tumour. Since all of these patients were referred, there may have been a referral bias. Patients with a poor performance status, poor Child–Pugh classification or advanced tumour stage are usually not given aggressive treatment. Although the AJCC T stage and the radiation dose were statistically significant factors on the log-rank test, the ECOG performance status was the only independent factor for survival on Cox regression analysis. No lesion factors affected survival. Thus, subcutaneous metastasis had a minimal impact on the survival of HCC patients. Performance status has been found to be an independent predictor of survival in a study dealing with the natural history of untreated HCC [30, 31]. The strategy for treating subcutaneous metastasis in HCC patients should be based on the patient's performance status. The survival of patients with HCC and subcutaneous metastasis was not statistically different from those patients with HCC referred to radiation therapy for other reasons, such as portal vein thrombosis and bone metastasis, although the case numbers varied. There were no deaths directly related to subcutaneous metastasis, and there was no evidence that subcutaneous metastasis was associated with a poor prognosis in patients with HCC.
In this study, only eight lesions (33.3%) had a pathological diagnosis recorded on the chart; thus one could question whether the lesions for which there was no pathological evidence were in fact metastases. However, the gross appearance of these lesions was similar, and there was no statistically significant difference in treatment response according to the presence of pathological evidence (Table 1
). Thus, it is reasonable to assume that the subcutaneous lesions for which there was no pathological diagnosis were in fact metastatic. Although a biopsy or aspiration cytology could have been easily performed, these procedures were not done due to the treating physicians' impression that most subcutaneous metastases were iatrogenic and the poor prognosis of the patients with HCC. It appears that the diagnosis of subcutaneous metastasis in patients with HCC could be carried out clinically, but there were too few cases in this study to make a definitive conclusion. As subcutaneous metastases are easily visible and palpable, a biopsy or aspiration could be easily performed. Therefore, whenever possible, pathological proof of the diagnosis of a subcutaneous mass in a patient with HCC should be obtained to confirm the diagnosis and gather data for further study.
In this study, the response to local radiation therapy of subcutaneous metastases from HCC was reviewed. The results were not disappointing. 20 of the 24 lesions (83.3%) achieved at least PR, and all symptomatic patients obtained relief. Compared with surgical excision, which could potentially eliminate all malignant cells, radiation therapy has certain advantages. The irradiated fields can be extended beyond the tumour with a safety margin that is not limited by concerns related to wound closure. Furthermore, patients are not exposed to the risks of anaesthesia, which is especially important among patients with a high prevalence of liver function impairment. The most serious sequela after radiation therapy was moist desquamation in the irradiated field; no systemic complications were noted. The moist desquamation was easily treated with a steroid-based ointment and healed spontaneously when further radiation therapy was withheld. Radiation therapy could be considered to be the non-invasive treatment of choice for subcutaneous metastasis of HCC, even to an asymptomatic lesion for prophylaxis, since it has an appropriate response rate and tolerable side-effects.
Based on the Mann–Whitney test for treatment response (Table 1), the ECOG performance status and the radiation dose affected the results, although 20 of 24 lesions (83.3%) achieved at least PR. Unexpectedly, typical lesion characteristics, such as tumour size, had no effect on the treatment response. This may be because subcutaneous metastases of HCC have excellent radiation sensitivity and that radiation therapy could be easily planned for these surface lesions. Because the treatments in this study were all intended to be palliative, the applied technique was only single-filed electron or opposite-field photon beam, which is easy and fast. In case the lesion is unable to be covered by the electron beam, the wedge-pair photon technique might provide a better dose distribution instead of opposite field. Since there was a direct dose–response trend for radiation therapy to a subcutaneous metastatic lesion in HCC, the treatment planning needs to be more delicate in the future. In this study, the two lesions with SD after radiation therapy both hold an ECOG performance status worse than 1 and a radiation dose less than 50 Gy. Radiation therapy was delivered by fractionation, so that patients with a better performance status had the opportunity of receiving more fractions of the radiation dose, ultimately resulting in a larger total dose. Radiation dose is a well-established prognostic factor for unresectable HCC [32]. In this study, ECOG performance status was not only an independent factor for survival, it was a significant factor for treatment response. Ideally, the tumour control rate increases with the radiation dose. Dose escalation markedly enhances the regression of tumours, but performance status is a determinant of dose escalation for local treatment. In any case, the prognosis of HCC patients with subcutaneous metastases depends on their performance status.
Although subcutaneous metastasis occurs rarely in HCC patients, its incidence may increase with improvements in the treatment of HCC that can provide excellent primary tumour control. In this study, radiation therapy was found to result in a satisfactory treatment response for HCC patients with subcutaneous metastasis. Thus, radiation therapy to subcutaneous metastasis could be the treatment of choice, particularly in patients with a good performance status who are treated with a radiation dose greater than 50 Gy; the treatment response is good, and the side-effect profile is acceptable. Larger studies are needed to determine the impact of subcutaneous metastases on the course of HCC, as well as to compare the results of radiation therapy and surgical interventions to establish a definitive treatment strategy.
Received for publication November 17, 2006.
Revision received January 30, 2006.
Accepted for publication February 5, 2006.
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Abstract
Introduction
