Peripheral hypereosinophilia in a patient with hepatocellular carcinoma. (Letters to the Editor).

To the Editor: Peripheral blood eosinophilia is a well-recognized but unusual manifestation of a variety of malignant conditions including acute leukemia, Hodgkin's disease, lymphoma, and several solid tumors such as carcinoma of the uterus, thyroid, kidney, stomach, lung, mesothelioma, and melanoma, (1-3) but few cases of hypereosinophilia associated with hepatocellular carcinoma have been reported. 1-4 In this letter, we describe a case of hepatocellular carcinoma accompanied by marked peripheral eosinophilia and eosinophilic infiltration into the bone marrow and liver without evidence of allergic disorders or parasitic infestation.

A 58-year-old man was admitted to our hospital in poor general condition because of increasing fatigue and weakness with poor appetite and 10-kg weight loss during a 1-month period. He was a cigarette smoker and consumed alcohol periodically. His medical history was negative. A physical examination revealed that he appeared cachetic with palpable hepatomegaly, and there was not any lymphadenopathy. Laboratory data were hemoglobin 172 g/L, white blood cell (WBC) count 106.4 >( 1 09/L, and differential of the WBC showed eosinophils 55%, neutrophils 27%, monocytes 3%, and lymphocytes 15%. The absolute eosinophil count was 58.52 X 109/L, and the platelet count 366 >( 109/L. Liver function test were aspartate aminotransferase 115 U/L, alanine aminotransferase 102 U/L, alkaline phosphatase 5,944 U/L, serum lactic dehydrogenase 2,052 U/L, [gamma]-glutamyltransferase 2,944 U/L, total bilirubin 6.12 mg/dl, direct bilirubin 4.02 mg/dl, and albumin 2.3 g/dl. Serum immunoglobulin E level was 33 U/ml, [alpha]-fetoprotein 2.67 ng/ml, and carcinoma embryonic antigen (CEA) 159.8 ng/ml. The hepatitis A, B, and C serologic examinations were negative.

Repeated examination of stool for ova and parasites were negative. All other routine laboratory studies were within normal limits. An abdominal ultrasonogram confirmed the presence of multiple large hypoechoic hepatic lesions, some lymphadenopathies, and moderate ascites. Histologic examination of the liver lesions was consistent with hepatocellular carcinoma with areas of cirrhosis and presence of prominent infiltration of mature eosinophils within tumor tissue. Bone marrow aspiration and biopsy performed showed only marked eosinophilopoiesis with increased numbers of eosinophil precursors without blasts. The cytogenetic studies were normal and negative for Philadelphia chromosome. The patient did not receive treatment because of his general condition and he expired within 10 days after the malignancy was pathologically confirmed.

Hepatocellular carcinoma may manifest various paraneoplastic syndromes and some reports describe hematologic changes due to hepatocellular carcinoma. (1) However, peripheral blood eosinophilia is not commonly associated with hepatocellular carcinoma and, to the best of our knowledge, fewer than 6 cases of hepatocarcinoma and eosinophilia have been reported. (1-4)

Hypereosinophilia is usually referred to as a paraneoplastic phenomenon and sometimes can be attributed to factors other than the tumor per se. (1-3,5) In our patient there was no identifiable causes for his eosinophilia, including no history of any medication before the beginning of his complaints, no evidence of drug-induced reactions, immunoallergic responses, eosinophilic parasitic infections, or radiation therapy. The only possible etiology was the hepatocellular carcinoma, which was quite advanced in stage with the multifocal involvement. In our case, three months earlier his blood count was normal and peripheral eosinophilia was the first manifestation of the cancer and heralded the onset of disseminated disease.

This patient had a classic picture of hepatocellular carcinoma with tumorassociated tissue eosinophilia in the liver and bone marrow occurred together with peripheral blood eosinophilia which could have prognostic significance. (2) Circulating eosinophilia is associated with disseminated, metastatic disease and hence signifies a poor prognosis, whereas tissue eosinophilia in advanced cancer has a better survival rate. (2)

The current pathogenesis of paraneoplastic peripheral eosinophilia appears to be a response to cytokine production and usually involves production of interletikin-5 (IL-5) within the tumor, either by malignant or by reactive cells, especially [CD.sup.4+] T-helper lymphocytes of type 2 ([TH.sub.2]). (5) A recent study has revealed that eosinophilia was likely to reflect the invasion of the tumour by reactive [TH.sub.2] lymphocytes, local accumulation and activation of which result in IL-5 production. (4,5) Eosinophilia, regardless of the underlying cause, commonly cause tissue damage once a critical level of eosinophilia is reached and treatment should be directed at the underlying cause once it has been identified. Although in the present case his condition did not allow to commence treatment and he died only ten days after a biopsy of liver showed signs of hepatocellular carcinoma, there is evidence of the rapid normalization of peripheral eosinophilia after hepatocellular carcinoma removal. (4) We emphasize that malignancies should always be ruled out in patients with unexplained peripheral eosinophilia, because they may well represent an important disease marker of advanced stage malignancy.

Jose Manuel Calvo Villas, MD

Department of Hematology

Samir Amine Salah, MD

Section of Gastroenterology

Department of Medicine

Jorge Cuesta Tovar, MD

Elena Carreter de Granda, MD

Francisco Sicilia Guillen, MD

Department of Hematology

Hospital General de Lanzarote

Arrecife de Lanzarote (Las Palmas de Gran Canaria)

Spain

References

(1.) Salame M, Rickacrt F, Deprez C, Van Gossum A, Cremer M. Hepatocarcinoma and hypereosinophilia [in French]. Acta Gastroenterol Beig 1988;51:169-172.

(2.) Yuen BH, Reyes CV, Rawal PA, Sosman J, Jensen J. Severe eosinophilia and hepatocellular carcinoma: An unusual association. Diagn Cytopathol 1995;13:151-154.

(3.) Chang WC, Liaw CC, Wang PN, Tsai YH, Hsueh S. Tumor-associatcd hypereosinophilia: Report of four cases. Changgeng Yi Xue Za Zhi 1996;19:66-70.

(4.) Balian A, Bonte E, Naveau S, Foussat A, Bouchet-Delbos L, Berrebi D, et al. Intratumoral production of interleukin-5 leading to parancoplastic peripheral cosinophilia in hepatocellular carcinoma. J Hepatol 2001;34:355356 (letter).

(5.) Samoszuk M. Easinophils and human cancer. Histol Histopathol 1997;12:807-812.