Fulminant hepatic failure and hepatomegaly caused by diffuse liver metastases from small cell lung carcinoma: 2 autopsy cases

respiratory investigation 51 (2013) 98 –102

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Case report

Fulminant hepatic failure and hepatomegaly caused by diffuse liver metastases from small cell lung carcinoma: 2 autopsy cases Kazuhide Satoa,n, Yoshihiro Takeyamaa, Taku Tanakab, Yasutaka Fukuia, Hideo Gondaa, Ryujiro Suzukia a

The Department of Respiratory Medicine, Toyohashi Municipal Hospital, Japan The Department of General Internal Medicine, Toyohashi Municipal Hospital, Japan

b

ar t ic l e in f o

abs tra ct

Article history:

Fulminant hepatic failure (FHF) is defined as a liver disease that causes encephalopathy

Received 7 September 2012

within 8 weeks of onset in the absence of pre-existing liver disease. Although liver

Received in revised form

metastases are commonly found in cancer patients, FHF secondary to diffuse liver

17 December 2012

infiltration is rare. Here, we report the rare autopsy cases of patients with small cell lung

Accepted 28 December 2012

carcinoma (SCLC) and secondary FHF. These patients presented with remarkable hepato-

Available online 26 February 2013

megaly and a near complete replacement of the liver parenchyma with metastatic tumor.

Keywords:

Neoplastic involvement of the liver should be considered in the differential diagnosis

Fulminant hepatic failure (FHF)

of FHF.

Small cell lung carcinoma (SCLC)

& 2013 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

Liver metastasis Hepatomegaly

1.

Introduction

Globally, lung cancer is the most common human malignancy and the leading cause of cancer deaths, with 1.6 million newly diagnosed cases and 1.378 million deaths annually (International Agency for Research on Cancer). Small cell lung carcinomas (SCLCs) account for 25% of diagnosed lung carcinomas. Approximately 70% of newly diagnosed SCLC patients initially present with an advanced disease stage [1,2]. Fulminant hepatic failure (FHF) is a liver disease that causes encephalopathy within 8 weeks of symptom onset in patients without prior liver disease. FHFs most commonly

result from viral hepatitis or drug toxicity and not from primary or metastatic carcinomas [3–6]. Although the liver is one of the most common metastatic sites for SCLC, mild to moderate liver disorder is often the only outcome. Liver disorders ranging from acute hepatic failure to FHF are rarely caused by diffuse parenchymal infiltration of SCLC [1,7–9]. Because of highly progressed disease states, clinical courses are usually too short to identify the causes, resulting in multi-organ failure. Diagnosis of hepatic infiltration in such patients presenting with FHF is difficult. High degrees of suspicion are required if there is no evidence of the primary disease.

n Correspondence to: Toyohashi Municipal Hospital, 50, Aza-Hakken-nishi, Aotake-cho, Toyohashi-shi, AICHI 441-8570, Japan. Tel.: þ81 532 33 6111; fax: þ81 532 33 6177. E-mail address: [email protected] (K. Sato).

2212-5345/$ - see front matter & 2013 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.resinv.2012.12.004

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respiratory investigation 51 (2013) 98 –102

We describe 2 autopsy cases of rapid FHF secondary to SCLC: one of an acute recurrence of SCLC and the other with unknown initial etiology. These 2 rare cases had contrasting clinical courses and very intriguing imaging findings that provide new insights.

2.

Case presentation

2.1.

Case 1

A 69-year-old Japanese male SLCL patient received 4 courses of chemotherapy (60 mg/m2 CPT-11, days 1, 8, and 15 and 80 mg/m2 CDDP, day 1). He showed good partial response (PR) to chemotherapy. No history of hepatitis, alcohol abuse, or drug allergy was noted. He was admitted for prophylactic cranial irradiation. During the irradiation, he complained of sudden epigastralgia and chest pain. Physical examination revealed arrhythmia, hepatomegaly, and bilateral pretibial edema, although he maintained alert consciousness. Followup examination showed elevated WBC, cardiac enzyme, and liver enzyme levels (Table 1, Case 1—Day 1). Serological tests for hepatitis virus, Epstein–Barr virus, (EBV) and cytomegalovirus (CMV) were negative. Abdominal ultrasonography showed only hepatomegaly (Fig. 1A). CT revealed marked hepatomegaly, although no space-occupying lesion (SOL) was apparent (Fig. 1B). Contrast-enhanced CT revealed diffuse multiple low-density areas (LDAs) in the liver (Fig. 1C). T2-weighted (Fig. 1D) and diffusion-weighted (DW; Fig. 1E)

MRI showed hepatomegaly with diffuse small high-intensity areas (HIAs) that were contrasted in the dynamic phase and washed-out in the late phase with gadolinium-based contrast media (Fig. 1F), suggesting that hepatomegaly resulted from diffuse malignant parenchymal infiltration. Follow-up percutaneous liver biopsy (Fig. 2A) and bone marrow puncture showed SCLC metastasis to the bone marrow and liver. Serum levels of NSE and ProGRP (SCLC tumor markers) were highly elevated (Table 1, Case 1—Day 2). On Day 3, the patient became drowsy and exhibited abnormal behavior, indicating the onset of encephalopathy due to FHF (Table 1, Case 1—Day 3). He died of severe liver dysfunction and multi-organ failure on Day 7 after the initial complaint (Table 1, Case 1—Day 7). Postmortem examination showed a markedly enlarged liver (3570 g), with multiple coarse micro-nodules (Fig. 2B). The cut surface had multiple tumor nodules of varying sizes (Fig. 2C). Microscopic analysis indicated SCLC metastasis. SCLC had extensively infiltrated the hepatic sinusoids and replaced the hepatic parenchyma (Fig. 2D). Within the bilateral lungs, kidneys, adrenal glands, spleen, and vertebrae, diffuse SCLC micro-metastases were observed.

2.2.

Case 2

A 63-year-old Japanese male patient was referred to our hospital with jaundice. He was a very heavy smoker with no history of hepatitis, alcohol abuse, or drug allergy. Follow-up examination revealed elevated liver enzyme levels (Table 1, Case 2—Day 1). Serological tests for hepatitis virus, EBV, and

Table 1 – Serological data from Cases 1 and 2. Case 1

AST (U/L) ALT (U/L) LDH (U/L) ALP (U/L) g-GTP (U/L) T-BIL (mg/dL) PT (%) PT-INR NH3 (mg/dL) NSE (ng/mL) ProGRP (pg/mL)

Day 1

Day 2

Day 3

Day 4

Day 5

Day 6

Day 7

272 412 1848

469 640 2105 514 554 2.9

453 626 2440 765 721 4.4

337 596 2697 920 816 5.5 66.6 1.59

242 441 1987 852 723 6.9 70 1.54 124

397 538 2012

8790 3728 11390 933 745 15.9 9.1 10.78 150 1265.7 7920

2.7 79 1.44

126 1585.8 3870

849 9.4

Case 2

AST (U/L) ALT (U/L) LDH (U/L) ALP (U/L) g-GTP (U/L) T-BIL (mg/dL) PT (%) PT-INR NH3 (mg/dL) NSE (ng/mL) ProGRP (pg/mL)

Day 1

Day 4

Day 5

Day 6

150 251 3040 1003 1585 4.1

175 232 3333 875 1522 5.9 63.5 1.44

185 233 3421 856 1543 6.4 60.2 1.5 113

196 235 4061 886 1372 6.1 58.6 1.53 167 2738.2 197000

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respiratory investigation 51 (2013) 98 –102

Fig. 1 – Abdominal ultrasonography, CT, and MRI. (A) Abdominal ultrasonography, (B) abdominal CT, (C) abdominal contrastenhanced CT, (D) abdominal T2-weighted MRI, (E) abdominal diffusion-weighted MRI, and (F) abdominal contrast-enhanced MRI in Case 1. (G) Abdominal ultrasonography, (H) abdominal CT, (I) abdominal contrast-enhanced CT, (J) chest CT of upper chest, (K) abdominal T2-weighted MRI, and (L) abdominal diffusion-weighted MRI in Case 2.

CMV were negative. Abdominal ultrasonography revealed only hepatomegaly (Fig. 1G). CT revealed marked hepatomegaly, although no SOL was apparent (Fig. 1H). Contrastenhanced CT revealed diffuse multiple LDAs in the liver (Fig. 1I), SOL in the right upper lung, and mediastinal lymphadenopathy (Fig. 1J), suggesting metastasis of the primary lung carcinoma to the liver. T2-weighted (Fig. 1K) and DW (Fig. 1L) MRI revealed hepatomegaly with diffuse HIAs, suggesting that hepatomegaly had resulted from diffuse malignant parenchymal infiltration. On Day 5, endobronchial ultrasonography-guided transbronchial needle aspiration (EUBS-TBNA) of an enlarged mediastinal lymph node was performed for primary carcinoma diagnosis. On Day 6, the patient became drowsy and liver encephalopathy

due to FHF was noted (Table 1, Case 2—Day 6). He died of severe liver dysfunction and multi-organ failure on Day 8 after admission. On Day 9, pathological analysis of the EBUS-TBNA specimen indicated SCLC. Postmortem examination revealed a markedly enlarged liver (2700 g), with multiple diffuse coarse micro-nodules. The cut surface had multiple tumor nodules of varying sizes (Fig. 2E). Microscopic analysis revealed SCLC metastasis. Extensive infiltration of the hepatic sinusoids and replacement of the hepatic parenchyma by SCLC were observed (Fig. 2F and G). The cut surface of the right lung revealed primary SCLC (Fig. 2H). Within the bilateral lungs (Fig. 2I), kidneys, adrenal glands, spleen, and vertebrae, diffuse SCLC micro-metastases were observed.

respiratory investigation 51 (2013) 98 –102

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Fig. 2 – Pathological analysis. (A) Hematoxylin-eosin staining (H–E) of a liver needle biopsy, (B) appearance of the liver during autopsy, (C) cut surface of the liver during the autopsy, and (D) H–E of the liver in Case 1. (E) Cut surface of the liver during the autopsy, (F) H–E of the liver, (G) magnified H–E of the liver, (H) cut surface of the right lung during the autopsy, and (I) H–E of the lung tumor in Case 2.

3.

Discussion

FHF mostly results from viral infections or hepatotoxin exposure. Viral hepatitis accounted for 70%, and drug toxicity, for 15% of FHF cases in a study [10], whereas malignant hepatic infiltrations accounted for only 0.4% of cases. In previous studies, FHF was the first clinical symptom of hepatic metastases from unknown carcinomas [11]. Malignant liver infiltrations are rare and therefore diagnosed after death. Metastatic involvement of the liver must be considered in the differential diagnoses of patients with hepatic failure and no history of viral hepatitis or hepatotoxin exposure. Hepatic metastases are reported in approximately 50% of patients who died of cancer. Rapid progression of SCLC to FHF is extremely rare, although SCLC is highly invasive and the liver is the most common target for metastatic tumors. In some FHF cases, tumors replace up to 90% of the liver without manifestation of jaundice. Comas develop in only 7.2% of metastatic liver disease patients, mostly in breast, gastric, and colon cancer or lymphoma patients [10]. In our 2 cases, postmortem examinations revealed diffuse hepatic sinusoidal invasion by the tumor cells with extensive liver parenchyma destruction. Massive sinusoidal infiltration and obliterative invasion of the hepatic vessels by malignant cells resulted in ischemia and hepatocyte necrosis. Subsequently, tumor cells extensively replaced normal liver parenchyma, resulting in hepatocyte destruction and FHF induction.

Cytokines from tumor cells play important roles in bile duct destruction and portal fibrosis, resulting in sinusoidal microcirculation obstruction and hepatocyte ischemia [7,11]. Imaging studies often fail to reveal malignancies in FHF patients because of diffuse hepatic involvement [1,12–14]. In case 1, contrast-enhanced abdominal CT revealed hypovascular nodules, not observed on plain CT. Hepatomegaly is easily observed on plain CT, unlike multiple nodules. Thus, contrastenhanced CT may be useful in detecting multiple metastases during evaluations for diffuse hepatomegaly. MRI is useful in detecting hepatic nodules when ultrasonography is unable to sufficiently differentiate diffuse intrasinusoidal metastases from other diseases, e.g., fatty liver or hepatitis [11]. In case 2, the nodules were clearly detected. The important difference between cases 1 and 2 was nodule size. Plain CT demonstrated 92% sensitivity for liver tumors 42 cm, but only 8% for tumors o2 cm. The sensitivity of contrast-enhanced CT and MRI is 20% and 33%, respectively, for liver tumors o2 cm [13]. Postmortem examinations showed diffuse and extensive replacement of hepatic parenchyma and sinusoidal infiltration by SCLC. Thus, revealing metastatic liver tumors using imaging modalities is often difficult. Serological analysis of the LDH:ALT ratio is very useful for distinguishing non-malignant FHF from SCLC-related FHF. For SCLC-related FHF, the LDH:ALT ratio is significantly increased, as seen in our 2 cases. Extremely high serum levels of LDH indicate diffuse liver parenchyma replacement and are associated with a high risk of FHF [1].

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Chemotherapy is the likely candidate therapy for SCLCrelated FHF. One report on encephalopathy described an apparently dramatic response to amrubicin administration, suggesting that early diagnosis and prompt administration of appropriate chemotherapy might improve survival in FHF patients [15]; however, FHF progresses rapidly, thereby limiting patient survival. In conclusion, SCLC manifesting as FHF is a rare but challenging clinical situation. Quick accurate diagnosis is important because treatment differs for SCLC-related FHF and FHF due to other common causes (i.e., viral hepatitis or hepatitis due to toxicities). Diffuse liver metastases must be considered for hepatomegaly observed in FHF patients, especially when other common causes are excluded.

Conflict of interest The authors have no potential conflicts of interest.

Acknowledgments We are grateful to Dr. Matsuyoshi Maeda, Dr. Toshio Kato, and Dr. Hiroyuki Hashimoto. This work was supported by CJLSG (Central Japan Lung Study Group).

references

[1] McGuire BM, Cherwitz DL, Rabe KM, et al. Small-cell carcinoma of the lung manifesting as acute hepatic failure. Mayo Clin Proc 1997;72:133–9. [2] Dearing MP, Steinberg SM, Phelps R, et al. Outcome of patients with small-cell lung cancer: effect of changes in staging procedures and imaging technology on prognostic factors over 14 years. J Clin Oncol 1990;8:1042–9.

[3] Harrison HB, Middleton 3rd HM, Crosby JH, et al. Fulminant hepatic failure: an unusual presentation of metastatic liver disease. Gastroenterology 1981;80:820–5. [4] Bernuau J, Rueff B, Benhamou JP. Fulminant and subfulminant liver failure: definitions and causes. Semin Liver Dis 1986;6:97–106. [5] Trey C, Davidson CS. The management of fulminant hepatic failure. Prog Liver Dis 1970;3:282–98. [6] Sugawara K, Nakayama N, Mochida S. Acute liver failure in Japan: definition, classification, and prediction of the outcome. J Gastroenterol 2012;47:849–61. [7] Rowbotham D, Wendon J, Williams R. Acute liver failure secondary to hepatic infiltration: a single centre experience of 18 cases. Gut 1998;42:576–80. [8] Terashima T, Matsuzaki T, Ogawa R, et al. Fluminant hepatic failure as the initial manifestation of small-cell lung cancer: report of 2 cases. Ann Cancer Res Ther 2008;16:16–20. [9] Gilbert J, Rutledge H, Koch A. Diffuse malignant infiltration of the liver manifesting as a case of acute liver failure. Nat Clin Pract Gastroenterol Hepatol 2008;5:405–8. [10] Rajvanshi P, Kowdley KV, Hirota WK, et al. Fulminant hepatic failure secondary to neoplastic infiltration of the liver. J Clin Gastroenterol 2005;39:339–43. [11] Athanasakis E, Mouloudi E, Prinianakis G, et al. Metastatic liver disease and fulminant hepatic failure: presentation of a case and review of the literature. Eur J Gastroenterol Hepatol 2003;15:1235–40. [12] Alexopoulou A, Koskinas J, Deutsch M, et al. Acute liver failure as the initial manifestation of hepatic infiltration by a solid tumor: report of 5 cases and review of the literature. Tumori 2006;92:354–7. [13] Miyaaki H, Ichikawa T, Taura N, et al. Diffuse liver metastasis of small cell lung cancer causing marked hepatomegaly and fulminant hepatic failure. Intern Med 2010;49:1383–6. [14] Ihara N, Yashiro N, Kinoshita T, et al. Diffuse intrasinusoidal liver metastasis of small cell lung cancer causing fulminant hepatic failure: CT findings-a case report. Radiat Med 2001;19:275–7. [15] Kaira K, Takise A, Watanabe R, et al. Fulminant hepatic failure resulting from small-cell lung cancer and dramatic response of chemotherapy. World J Gastroenterol 2006;12:2466–8.