Medical and Pediatric Oncology 20:349-351 (1992)

Neuroendocrine Carcinoma in a Patient With Hairy Cell Leukemia: A Case Report Karen K. Ballen, MD, Rosa Canoso, MD, Marcel Seiler, Andrew Neish, MD, and Kenneth A. Bauer, MD Second malignancies are common in hairy cell leukemia. We report a case of a neuroendocrine carcinoma arising in a patientwho had been diagnosed with hairy cell leukemia 6 years earlier. This case is the first

MD,

report of these two tumors’ occurring together. The pathogenetic basis for the presence of these two uncommon tumors in o u r patient is discussed. o 1992 WiIey-Liss, Inc.

Key words: neuroendocrine tumor, second malignancies, pathogenetics

spleen palpable below the umbilicus. The rest of the exam was unremarkable. Laboratory data revealed a Hairy cell leukemia (HCL) is a malignant lymphoprohemoglobin of 8 g/dl, platelet count of 208,OOO/pl,and liferative disorder characterized by splenomegaly , pana WBC of 77,00O/pl with less than 1% monocytes. Liver cytopenia, and distinctive mononuclear cells. Second function tests were normal. malignancies are commonly associated with HCL, ocAt laparotomy , multiple whitish nodules were noted curring in 9% of patients with HCL [I]. We report the on the hepatic and splenic surface; the pancreas and first patient with HCL who later developed a neuroenbowel appeared normal. The spleen, an accessory spleen, docrine tumor. gallbladder, and a liver nodule were removed. Pathology revealed a 1,100 g spleen with diffuse infiltration by CASE REPORT hairy cells. The nodules were composed of well-differentiated trabecular glands, which displayed focal posiA 65-year-old man with hairy cell leukemia was tivity for mucin and chromogranin, and absence of admitted for cholecystectomy and splenectomy . He preimmunoreactivity for insulin, glucagon, somatostatin, sented 6 years earlier with chest pain, at which time he and gastrin (Fig. 1). Electron microscopy revealed typiwas noted to have splenomegaly with a hemoglobin of 12 cal neurosecretory granules of a neuroendocrine tumor g/dl, a white blood cell (WBC) count of 26,00O/pI, and (Fig. 2). a platelet count of 343,00O/pl. Peripheral blood smear Postoperative evaluation included an abdominal comand bone marrow revealed a large number of lymphoputed tomography scan, which was remarkable for new cytes with hairy projections. Tartrate resistant acid phosfocal filling defects in the liver and a normal pancreas, A phatase (TRAP) stain on the bone marrow was positive. urine collection for 5-hydroxyindole acetic acid (5He did well for 2 years but then noted fatigue, with a HIAA) was normal with an excretion of 1.5 mg per 24 WBC of 292,0OO/pl. He was treated with alpha interhours (normal range 0.5-9 mg/24 hours). Because the feron, which reduced the WBC to 90,00O/pl. However, the drug was discontinued secondary to thrombocytopenia. He received pulse chlorambucii, 14 mg daily for 4 days every 28 days for 15 cycles, for a total of 814 mg. He responded well, with WBC falling to 80,0OO/pland From the Hematology Division, Department of Medicine (K.K.B.), and the Department of Pathology (A.N.), Brigham and Women’s platelets remaining at 200,0OO/p,l. Hospital, and Departments of Medicine (R.C., K.A.B.) and Pathology Two months prior to admission, he complained of (M.S.), BrocktoniWest Roxbury Veterans Administration Medical right upper quadrant pain; ultrasound revealed gallstones. Center, Harvard Medical School, Boston, MA. He continued to have biliary colic and therefore was Received February 7, 1991; accepted August 6 , 1991. admitted for elective cholecystectomy and splenectomy. Address reprint requests to Karen K. Ballen, MD, Division of He denied weight loss, flushing, wheezing, and diarrhea. Hematology, Brigham and Women’s Hospital, 75 Francis Street, His abdomen was protuberant with a 20 cm liver and Boston, MA 021 15. 0 1992 Wiley-Liss, Inc. INTRODUCTION

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Fig. 1. Splenic nodule showing well-differentiated trabecular glands (hematoxylin and eosin; original magnification, X 125).

Fig. 2. Electron micrograph of a neuroendocrine tumor cell from a splenic metastasis. There are abundant neurosecretory granules averaging 125 nm in diameter in the cytoplasm of the cell.

Hairy Cell Leukemia-Neuroendocrine Tumor

patient is currently asymptomatic, he is being followed with no specific therapy for the neuroendocrine tumor. DISCUSSlON

This patient was found to have a neuroendocrine tumor 6 years after the diagnosis of HCL. Neuroendocrine carcinomas are a diverse group of tumors which include carcinoid and islet cell tumor of the pancreas, and have typical neurosecretory granules. Although pathology cannot distinguish among the various types of neuroendocrine carcinomas, the presence of liver metastases, the normal appearance of the pancreas at surgery, the degree of chromogranin positivity, and the lack of symptoms, all suggest a carcinoid tumor in our patient. Carcinoids, particularly those originating in the hindgut, often are associated with normal 5-HIAA urine collections and no flushing or diarrhea [2]. Second malignancies have been described in HCL. Jacobs et al. reviewed 172 patients with HCL; 15 were found to have a second malignancy (8.7%) [I]. Four cases were skin cancer, three lung, and one each of colon, pancreas, prostate, melanoma, renal cell carcinoma, squamous cell carcinoma of the lip, Hodgkin’s disease, and myelodysplastic syndrome. In one patient, the malignancy occurred before the diagnosis of HCL. Six cases were diagnosed within 1 year of the diagnosis of HCL; in eight patients the second malignancy followed the diagnosis of HCL by more than 1 year. Five of these eight patients were treated with chlorambucil. These eight patients all had an absolute monocyte count less than 2001p.1. Large cell lymphoma [ 3 ] ,multiple myeloma [4], gastric adenocarcinoma, and papillary cancer of the thyroid 1.51 have also been reported in patients with HCL. The etiology for secondary malignancies in HCL is not clear. The chronic use of alkylating agents or the immunologic defects associated with the underlying disease may be responsible for this phenomenon. The Polycythemia Study Group found that the risk of leukemia in polycythemia Vera patients was 13.5 times greater in those patients treated with chlorambucil than in those patients treated with phlebotomy alone [6]. The risk of leukemia was higher in patients treated with higher doses and for longer periods of time. Seventy-five percent of the cases of the leukemia occurred after three years of treatment with chlorambucil [6]. Lymphoma, lung cancer, squamous cell skin cancer, myelofibrosis, and carcinoma of the gallbladder have all been reported following chlorambucil therapy for malignant and non-

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malignant diseases [7]. Though our patient was treated with chlorambucil for 15 months, a neuroendocrine tumor has not been reported to date following treatment with this drug. Immunologic defects may play a role in the development of second malignancies in patients with HCL. Monocytopenia is a common feature of HCL and is important in the pathogenesis of recurrent infections in these individuals. Monocytes do have cytotoxic activity against tumor cells and may be important in tumor surveillance [ I ] . Natural killer (NK) cells are also active in tumor surveillance [ 5 ] . NK activity is decreased in HCL patients [8]. The NK defect appears not to be quantitative but related to a functional impairment [9]. An increased number of second malignancies have been reported with other B cell lymphoproliferative disorders. such as lymphoma. The defect in NK activity has been suggested as a possible explanation [ 3 ] . Hairy cell leukemia and neuroendocrine carcinoma are uncommon tumors; it is possible that these immune defects may predispose to the occurrence of a second malignancy. In our patient, the HCL preceded the neuroendocrine carcinoma. Chlorambucil may have been a precipitating factor, but it is more likely that immunological defects associated with HCL predisposed to a second malignancy.

REFERENCES I. Jacobs RH. Vokes EE, Golomb HM: Second malignancies in hairy cell leukemia. Cancer 56:1462-1467, 1985. 2. Feldman JM: Carcinoid tumors and syndrome. Semin Oncol 12:237-246, 1987. 3 . Downing JR, Grossi CE, Smedberg CT, Burrows PD: Diffuse large cell lymphoma in a patient with hairy cell leukemia. Blood 67:739-744, 1986. 4. Lawlor E, Willoughby R, O’Briain DS, Daly PA: Multiple neoplasms in hairy cell leukaemia. Acta Haematol (Basel) 72:5760, 1984. 5. Stewart DJ, Keating MJ: Second malignancies in hairy cell leukemia. Am J Hematol 13:167-169, 1982. 6. Berk PD, Goldberg JD, Silverstein MN, et al.: Increased incidence of acute leukemia in polycythemia Vera associated with chlorambucil therapy. N Engl J Med 304:441-447, 1981. 7. Palmer RJ, Denman AM: Malignancies induced by chlorambucil. Cancer Treat Rev I1:121-129, 1984. 8. Doane LC, Ratain MS, Golomb HM: Hairy cell leukemia. Hematol Oncol Clin North Am 4:489-502, 1990. 9. Trentin C , Zanrbello R, Agostini C, et al.: Mechanisms accounting for the defective natural killer cell activity in patients with hairy cell leukemia. Blood 75:1525-1530, 1990.

Neuroendocrine carcinoma in a patient with hairy cell leukemia: a case report.

Second malignancies are common in hairy cell leukemia. We report a case of a neuroendocrine carcinoma arising in a patient who had been diagnosed with...
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