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Hepatocellular carcinoma metastases to the epidural space.

Metastases from hepatocellular carcinoma (HCC) were generally considered to be rare in the past, because the carcinoma had an aggressive clinical course, with only 10% of AJCC stage I patients surviving 5 years. (1) When metastases did occur, common sites included the adjacent organs of lung, lymph nodes, and bone. (2) With the advent of more effective therapeutic and palliative treatments, the outlook for HCC patients has improved, and metastases are becoming an increasingly relevant consideration. (3) Survival may be prolonged, especially in developed countries, where resources allow for more aggressive and costly adjuvant treatment regimens. (4) Longer patient survival might allow more widespread metastatic disease to emerge prior to demise.

We recently reported 3 white men native to the United States who developed intracranial metastases due to HCC, necessitating neurosurgical resection. (5) We predicted that brain metastases from HCC might be increasingly seen by physicians in the United States as patients began to enjoy longer survivals. (5) In the present study, we document our experience with a second, very different pattern of nervous system involvement from HCC: epidural and bony spine involvement. Both patients were women who were hepatitis B and C negative and presented with paresthesia, back pain, or radicular pain due to their epiduralspace metastatic disease. In both instances, the epidural space represented the first metastatic disease noted after identification of the primary HCC. To date, there are very few reports of epidural-space metastases in the literature, and most have come from Asian countries where HCC is endemic. (2,6-12) We suspect that other US referral institutions will soon see this second pattern of nervous system involvement with spinal cord or nerve root compression, if they have not done so already.

MATERIALS AND METHODS

Cases were accrued via a computer-directed search of the University of Colorado at Denver Pathology Department database for the years 1991 to 2008, inclusive, linking the disease process--"hepatocellular carcinoma"--with key words referable to the potential site of disease involvement in the central nervous system (ie, "spinal cord," "bone," and "soft tissue," with the last term included to pick up any sites, such as epidural space, possibly coded as soft tissue). The years 1991-2008 were chosen based on the accuracy of the coding of specimens performed during this time period. These 2 cases were the only ones disclosed in which HCC manifested a vertebral spine or epidural site location in our departmental files. In comparison, only 2 bony metastases from HCC not involving spine were discovered in our surgical pathology files: 1 to rib and 1 to sacrum. For perspective on these numbers, it can be noted that our institution is a referral hospital for liver transplantation in this region, and during this same time period, 277 examples of liver biopsies or liver explants with the diagnosis of "hepatocellular carcinoma" were identified in our surgical pathology files. Clinical information was obtained from the hospital medical records and personal communication with clinicians who cared for these patients.

Tissues were fixed in 10% formalin, embedded in paraffin, and cut at 4 [micro]m. All cases were immunohistochemically stained for HepPar-1 (monoclonal; 1:800; Dako, Carpinteria, California), a newer antibody that demonstrates very high sensitivity for HCC (13); cytokeratin 7 (monoclonal; 1:800; Dako); cytokeratin 20 (monoclonal; 1:200; Dako); CAM 5.2 (monoclonal; prediluted; Becton Dickinson, San Jose, California); carcinoembryonic antigen (polyclonal; 1:2 dilution of a predilute from Signet, Dedham, Massachusetts); and [alpha]-fetoprotein (AFP; polyclonal; 1:2 dilution of a predilute from Signet). Appropriate positive and negative controls were included for each antibody.

PATHOLOGIC FINDINGS Clinical Histories

Patient 1.--Patient 1 is a 55-year-old woman diagnosed with HCC in August 2006 after emergent surgery for a ruptured, multifocal liver tumor. The patient did not have any identifiable risk factors for HCC; specifically, she was negative for hepatitis B and C and had no cirrhosis. She was initially treated with a partial right hepatectomy and radiofrequency ablation of the liver margin. Because of recurrence of liver lesions, she subsequently underwent additional surgical treatment with radiofrequency ablation in May 2007 and 2 chemoembolization procedures (September and October 2007). The patient was followed closely by medical oncology and noted to have reasonably good clinical progress on the multiple-kinase inhibitor sorafenib and no evidence of tumor progression on repeated imaging of her liver. The patient's AFP showed mild increases but remained within the normal reference range; the highest value of 4.7 ng/mL was reached in February 2008. In June 2008, the patient presented to the hospital with a 6-month history of progressively worsening radicular-type neck pain. Magnetic resonance imaging of her cervical spine revealed a C7 lesion with extension into the epidural and paraspinal space, with resulting moderate spinal stenosis at C6/7 and C7/T1 and moderate to severe frontal narrowing at C7 and C8 exit foramina (Figure 1, A and B). The patient was treated with complete resection of the metastasis in July 2008, because positron emission tomography and further magnetic resonance imaging did not detect additional lesions. She remains alive at the time of submission of this report, 2 months after the diagnosis of her metastatic disease.

Patient 2.--Patient 2 is a 52-year-old woman who was diagnosed with autoimmune hepatitis in 1998 that progressed to cirrhosis and end-stage liver disease, necessitating a liver transplantation in June 2006. Prior to the transplantation (January 2006), the patient was diagnosed with HCC when computed tomography imaging revealed a 2-cm, hyperintense lesion in her right posterior lobe of liver in the setting of elevated AFP. In March 2006, she was treated with chemoembolization. Her explanted liver contained a focus of poorly differentiated HCC, 7.5 cm in greatest dimension, with necrosis consistent with chemoembolization and mixed micronodular and macronodular cirrhosis from her autoimmune hepatitis. The patient was negative for other HCC risk factors, including hepatitis B and C. At the time of HCC diagnosis, the patient's AFP was 1275.8 ng/mL, a marked increase from an October 2004 value of 14.2 ng/mL. The AFP receded after the transplantation to 371.4 ng/mL (April 2006), but by July and December 2006 it was again trending upward, with values of 630.4 and 2608.6 ng/mL, respectively. She did reasonably well until December 2006, when the patient presented to the hospital with a 3-week history of progressive low back pain and episodes of paresthesia in her right leg. Magnetic resonance imaging from an outside hospital had revealed an L1 spinal and paraspinal minimally enhancing mass concerning for neoplasm. At our institution, a computed tomography--guided fine-needle aspiration with core biopsies confirmed an osteolytic lesion and soft tissue mass positive for metastatic HCC. Of note, at that time she also had a lesion in her proximal femur suspicious for metastatic disease. No resection was performed. The patient returned to her hometown for follow-up care with her medical oncologist; specific details of any additional care are not available. She eventually succumbed to her illness in November 2007, 11 months after the detection of her metastatic disease.

Findings

In patient 1, the primary liver tumor was multifocal (with the largest nodule measuring 11 cm) and moderately differentiated, with a trabecular pattern. It extended through the hepatic capsule and invaded the vasculature. The metastatic epidural lesion histologically resembled the primary liver tumor, with a trabecular pattern of polygonal cells with abundant granular eosinophilic cytoplasm (Figure 1, C). The nuclei had irregular, thickened borders and contained coarse chromatin and prominent nucleoli. Several mitotic figures also were seen (Figure 1, D). CAM 5.2, HepPar-1, and cytokeratin 7 showed diffuse, positive immunoreactivity (Figure 1, E and F). Immunohistochemical reactions with cytokeratin 20 and carcinoembryonic antigen were focally positive. [alpha]-Fetoprotein immunoreactivity was not identified.

In patient 2, the primary liver tumor was solitary (7.5 cm in greatest dimension) and poorly differentiated (Figure 2, A). There was no vascular invasion or lymph node metastasis. Cytology of the metastatic epidural lesion showed polygonal cells with central nuclei and increased nuclear to cytoplasmic ratio. Many atypical, "naked" tumor cell nuclei also were present (Figure 2, B). The cell block recapitulated the trabecular architecture of the lesion and showed numerous mitotic figures (Figure 2, C). Immunostaining with HepPar-1 (Figure 2, D) and CAM 5.2 was diffusely positive. Immunohistochemical reactions with cytokeratin 7, cytokeratin 20, carcinoembryonic antigen, and AFP were focally positive, an immunophenotypic profile typical of HCC. (13)

Comment

These 2 patients were known to have HCC prior to developing back pain, paresthesia, or radicular pain several months after their initial diagnosis. Nevertheless, on review of the clinical records, it was clear that there was a delay between the temporal onset of symptoms and the recognition and diagnosis of metastatic epidural and spine disease by the clinicians following the patients. Patient 1 first noticed radicular-type neck pain symptoms in December 2007, 16 months after the diagnosis of her primary disease. She was not diagnosed with HCC metastatic disease until 6 months later, however, because her symptoms were attributed initially to residual musculoskeletal strain from lifting a heavy box. She was first treated with cyclobenzaprine hydrochloride and ibuprofen as needed, and at the time of diagnosis she was on a daily regimen of pregabalin and celecoxib and had even visited a chiropractor for persistent symptoms. In patient 2, only 3 weeks had elapsed between the onset of her back pain symptoms and the diagnosis of metastatic epidural and spine disease; however, of note, 5 months prior to diagnosis of metastatic disease, her AFP was elevated compared with her posttransplantation value.

The fact that clinicians in the United States do not recognize epidural space and spinal metastatic disease as a feature of HCC is not surprising, because few reports from the United States have been forthcoming. (2,8,9) Indeed, on literature review, we were only able to document 8 other cases in the English-language literature, mostly from patients native to endemic areas of disease in Asia (Table). Kim et al (10) reported the incidence of clinically detected spinal epidural metastases as 0.4% (11 of 3100) of HCC patients. There does not seem to be a strong predilection for cervical-level versus thoracic-level versus lumbosacral-level involvement (Table). There is a dearth of large autopsy studies on HCC in the literature to provide further information regarding patterns of metastatic spread at the end stage of the disease.

[FIGURE 1 OMITTED]

[FIGURE 2 OMITTED]

Although HCC is relatively uncommon in the United States, it is a major health problem worldwide. Hepatocellular carcinoma ranks as the sixth most common cause of cancer worldwide and accounts for approximately 626 000 new cancer cases (5.7% of all new cancers diagnosed) per year. (14,15) More striking, it is the third most common cause of cancer mortality. Most cases of HCC occur in males (2.5:1 ratio) (14) and are attributable to hepatitis B or C infection, but other well-established risk factors include alcoholic cirrhosis and exposure to aflatoxins. (16) Hepatocellular carcinoma remains endemic in Asia, Southeast Asia, and sub-Saharan Africa, although increased rates of hepatitis B immunization and reduction of aflatoxin exposure have begun to alleviate some of the disease burden in these areas. (14,17) In contrast, the incidence of HCC is increasing in many developed areas of the world, including the United States and Europe. (16) In the United States alone, the incidence of HCC has nearly doubled during the last 3 decades, in part because of the rising incidence of chronic hepatitis C infections. (14,17) Neither of our patients had hepatitis B or C as her risk factors for cirrhosis but, nevertheless, if cirrhosis increases from any cause in our population, and specifically from hepatitis C infection, it is not unreasonable to think that clinicians and pathologists will start to encounter HCC--and its unusual manifestations--with greater frequency in the near future.

For both of our patients, an added diagnostic difficulty may have been that their epidural and spinal metastases were the first presentation of any metastatic disease, rather than the more common sites of HCC spread to adjacent lung or lymph nodes. The first patient in our study underwent gross total resection of her cervical mass; this was both a therapeutic and a diagnostic procedure. In contrast, the second patient was diagnosed by fine-needle aspirate and core biopsies. She did not undergo a resection but still survived 11 months after the diagnosis of metastatic spinal disease. As more patients are accrued with epidural and bony spine metastases from HCC, better information will be forthcoming about optimal treatment for the disease. At this point, however, it is important to alert pathologists, oncologists, and neurosurgeons to this potential pattern of HCC spread. We suggest that new-onset neck or back pain--especially with symptoms of paresthesia, radiculopathy, or cord compression--in the setting of HCC warrants prompt investigation for HCC metastases to the spine and epidural space.

We thank Lisa Litzenberger, arts professional, for photographic expertise.

References

(1.) Cance WG, Stewart AK, Menck HR. The National Cancer Data Base Report on treatment patterns for hepatocellular carcinoma. Cancer. 2000;88(4):912-920.

(2.) Katyal S, Oliver JH, Peterson MS, Ferris JV, Carr BS, Baron RL. Extrahepatic metastases of hepatocellular carcinoma. Radiology. 2000;216(3):698-703.

(3.) El-Serag HB, Marrero JA, Rudolph L, Reddy KR. Diagnosis and treatment of hepatocellular carcinoma. Gastroenterology. 2008;134(6):1752-1763.

(4.) Llovet JM, Ricci S, Mazzaferro V, et al. SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4): 378-390.

(5.) Seinfeld J, Wagner AS, Kleinschmidt-DeMasters BK. Brain metastases from hepatocellular carcinoma in US patients. J Neurooncol. 2006;76:93-98.

(6.) Chen SF, Tsai NW, Lui CC, et al. Hepatocellular carcinoma presenting as nervous system involvement. Eur J Neurol. 2007;14(4):408-412.

(7.) Doval DC, Bhatia K, Vaid AK, et al. Spinal cord compression secondary to bone metastases from hepatocellular carcinoma. World J Gastroenterol. 2006; 12(32):5247-5252.

(8.) Garcia VA, Castillo R. Asymptomatic advanced hepatocellular carcinoma presenting with spinal cord compression. DigDis Sci. 2005;50(2):308-311.

(9.) Kantharia B, Nizam R, Friedman H, Vardan S. Case report: spinal cord compression due to metastatic hepatocellular carcinoma. Am J Med Sci. 1993;306(4): 233-235.

(10.) Kim M, Na DL, Park SH, Jeon BS, Roh JK. Nervous system involvement by metastatic hepatocellular carcinoma. J Neurooncol. 1998;36(1):85-90.

(11.) Tamaki K, Shimizu I, Urata M, et al. A patient with spinal metastasis from hepatocellular carcinoma discovered from neurological findings. World J Gastroenterol. 2007;13(19):2758-2760.

(12.) Yang WT, Yeo W, Leung SF, Chan YL, Johnson PJ, Metreweli C. MRI and CT of metastatic hepatocellular carcinoma causing spinal cord compression. Clin Radiol. 1997;52(10):755-760.

(13.) Geller SA, Dhall D, Alsabeh R. Application of immunohistochemistry to liver and gastrointestinal neoplasms: liver, stomach, colon, and pancreas. Arch Pathol Lab Med. 2008;132(3):490-499.

(14.) Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol. 2006;24(14): 2137-2150.

(15.) Parkin DM, Bray F, Ferlay J, Pisani P. Global Cancer Statistics, 2002. CA Cancer JClin. 2005;55(2):74-108.

(16.) El-Serag HB. Hepatocellular carcinoma: an epidemiologic view. J Clin Gastroenterol. 2002;35(5)(suppl 2):S72-S78.

(17.) Faruque A, Perz JF, Kwong S, Jamison PM, Friedman C, Bell BP. National trends and disparities in the incidence of hepatocellular carcinoma, 1998-2003. Prev Chronic Dis. 2008;5(3):A74.

Hilary Somerset, MD; J. Peter Witt, MD; Bette K. Kleinschmidt-DeMasters, MD

Accepted for publication February 12, 2009.

From the Departments of Pathology (Drs Somerset and Kleinschmidt-DeMasters), Neurosurgery (Drs Witt and Kleinschmidt-DeMasters), and Neurology (Dr Kleinschmidt-DeMasters), University of Colorado Health Sciences Center, Aurora.

The authors have no relevant financial interest in the products or companies described in this article. Reprints: Bette K. Kleinschmidt-DeMasters, MD, Pathology, Neurology, and Neurosurgery, University of Colorado at Denver and Health Science Center, 12605 E 16th Ave, Rm 3017, PO Box 6510, Aurora, CO 80045 (e-mail: bk.demasters@uchsc.edu).
Reported Cases of Hepatocellular Carcinoma (HCC) Metastases to the
Epidural Space

Source, y (Region of                      Clinical Presentation and
Origin of Patients)      Age, y/Sex            Symptom Duration

Chen et al, (6) 2007   58/M             Neck pain, left upper limb
  (Taiwan)                                weakness (21 d)
                       54/M             Paraparesis (5 d)
                       36/M             Paraparesis (4 d)
Doval et al, (7)       55/M             Lower back pain and
  2006 (India)                            generalized weakness (20 d)
                       52/M             Right hip pain, paraplegia
                                          with loss of bladder and
                                          bowel control (not
                                          specified)
                       70/M             Weakness of bilateral lower
                                          limbs (not specified)
                       62/M             Radicular neck and lower back
                                          pain (1 mo)
Garcia and Castillo,   49/M             Low back pain (2 wk) and
  (8) 2005 (United                        inability to walk (1 d)
  States)
Kantharia et al, (9)   45/M             Low back pain and left flank
  1993 (United                            pain (not specified)
  States)
Katyal et al, (2)      Not specified    Not specified
  2000; 22 cases
  (United States)
Kim et al, (10)        34-73/           Myelopathy, including back
  1998; 11 cases         10 M, 1 F        pain, neck pain,
  (Korea)                                 paresthesia, or progressive
                                          weakness, with sphincter
                                          dysfunction in 7 patients
                                          and radiculopathy in 4
                                          (not specified)
Tamaki et al, (11)     67/M             Lumbar pain, weakness of lower
  2007 (Japan)                            limbs, gait disturbance
                                          (4 mo)
Present study          55/F             Radicular-type neck pain
  (United States)                         (6 mo)
                       52/F             Low back pain and right leg
                                          paresthesia (3 wk)
Yang et al, (12)       37/M             Low back pain and right leg
  1997 (Hong Kong)                        paresthesia (4 mo)
                       47/F             Low back pain (3 mo)
                       31/M             Right hip and pelvis pain
                                          (not specified)
                       64/M             Signs of spinal cord
                                          compression (not specified)
                       55/M             Left upper limb weakness,
                                          paresthesia, and pain in
                                          C5-7 distribution (not
                                          specified)

Source, y (Region of
Origin of Patients)      Age, y/Sex                Location

Chen et al, (6) 2007   58/M             C7 with cord compression
  (Taiwan)             54/M             T3-7 with cord compression,
                                          and paraverteral mass with
                                          intraspinal extension
                       36/M             T3 with cord compression
Doval et al, (7)       55/M             T2-3, L1, L5, S1, S3, and
  2006 (India)                            epidural deposits with cord
                                          compression at T2 and T3
                       52/M             T2, T5, T6, L3 with cord
                                          compression
                       70/M             T4 and T5 with cord
                                          compression
                       62/M             C5-6, T9, T11-12, L4 with
                                          cord compression and
                                          epidural-space soft tissue
                                          mass at L4
Garcia and Castillo,   49/M             T9 with cord compression
  (8) 2005 (United
  States)
Kantharia et al, (9)   45/M             T10 with cord compression and
  1993 (United                            paraspinal mass extending
  States)                                 into paraspinal soft tissue
                                          and epidural space
Katyal et al, (2)      Not specified    Thoracic, lumbar, and sacral
  2000; 22 cases                          spine
  (United States)
Kim et al, (10)        34-73/           C3 to S1, most common at
  1998; 11 cases         10 M, 1 F        thoracic level
  (Korea)
Tamaki et al, (11)     67/M             Diffusely present from
  2007 (Japan)                            medullary cone to cauda
                                          equina and located mostly in
                                          the spinal canal at middle
                                          to lower lumbar level with
                                          cord compression
Present study          55/F             C7 with extension into the
  (United States)                         epidural and paraspinal
                                          space
                       52/F             L1 spinal and paraspinal mass
Yang et al, (12)       37/M             L3 and large soft tissue mass
  1997 (Hong Kong)                        at T12/L1
                       47/F             T4 and T5 with cord
                                          compression
                       31/M             T12 with cord compression and
                                          paraspinal soft tissue mass
                       64/M             L1 with epidural involvement
                                          from T11 to L2
                       55/M             C7 and paraspinal soft tissue
                                          mass

Source, y (Region of                    Survival Time,
Origin of Patients)      Age, y/Sex         mo (a)

Chen et al, (6) 2007   58/M              9
  (Taiwan)             54/M              7
                       36/M              1
Doval et al, (7)       55/M              5 (primary)
  2006 (India)         52/M             11 (primary)
                       70/M              4 (primary)
                       62/M              3 (primary)
Garcia and Castillo,   49/M              1 (both)
  (8) 2005 (United
  States)
Kantharia et al, (9)   45/M              0.3 (both)
  1993 (United
  States)
Katyal et al, (2)      Not specified    Not specified
  2000; 22 cases
  (United States)
Kim et al, (10)        34-73/            1.8 (mean
  1998; 11 cases         10 M, 1 F        survival
  (Korea)                                 time)
Tamaki et al, (11)     67/M              0.4
  2007 (Japan)
Present study          55/F             >2 (still
  (United States)                         living)
                       52/F             11
Yang et al, (12)       37/M              1.2
  1997 (Hong Kong)     47/F              2.2
                       31/M              2
                       64/M             Not specified
                       55/M              1

(a) Survival time after diagnosis of HCC epidural metastatic disease
or, in parentheses, after primary diagnosis or after simultaneous
diagnosis of both primary and metastasis, as specified.
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Title Annotation:Case Reports
Author:Somerset, Hilary; Witt, J. Peter; Kleinschmidt-DeMasters, Bette K.
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Report
Date:Dec 1, 2009
Words:3412
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