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Two cases of adult t-cell leukemia associated with acute pancreatitis due to hypercalcemia
1
CASE REPORTS
Two Cases of Adult T-Cell Leukemia Associated with Acute Pancreatitis due to Hypercalcemia YASUNOBU DAZAI, M.D., ICHIJIRO KATOH, M.D., YUJI HARA, M.D., RYOICHI YOSHIDA, M.D., Yawatahama, Japan, KENJI KURIHARA, M.D., Uwajima, Japan
We report two cases of adult T-cell leukemia associated with acute pancreatitis and hypercalcemia. After sudden onset of epigastralgia, acute pancreatitis and hypercalcemia were found in both patients. There were no diseases that could explain the acute pancreatitis except for hypercalcemia probably due to adult T-cell leukemia. Thus we considered that hypercalcemia due to adult T-cell leukemia had led to acute pancreatitis. This is the first report of such a complication in adult T-cell leukemia.
From the Department of Internal Medicine (YD. IK. YH, RY). Yawatahama City General Hospital. Yawatahama, Japan, and the Depariment of Pathology (KK), Uwaiima Municipal Hospital, Uwajima. Japan. Requests for reprints should be addressed to Yasunobu Dazai, M.D., Department of Internal Medicine, Yawatahama City General Hospital, Oohira. Yawatahama, Ehime 796, Japan. Manuscript submitted March 15. 1990. and accepted in revised form July 12. 1990.
dult T-cell leukemia is a human T-cell leukemia virus type I-associated leukemia endemic in southern Japan and the Caribbean basin [l-3]. It has several characteristics including convoluted Tlymphocyte nuclei, positive antibody to adult T-cell leukemia virus-associated antigen, and a high frequency of hypercalcemia. As to hypercalcemia as one of the causes of acute pancreatitis [4], there has been no report of acute pancreatitis caused by hypercalcemia due to adult T-cell leukemia. Here we report two cases of adult T-cell leukemia associated with acute pancreatitis due to hypercalcemia.
A
CASEREPORTS Patient 1 A 39-year-old Japanese man, born in Yawatahama City, Ehime prefecture, presented to Yawatahama City General Hospital in May 1988 with a complaint of tinea unguium. He had no history of previous illness, drug abuse, or blood transfusion. His peripheral blood revealed positivity for serum antibody to adult T-cell leukemia virus-associated antigen and a white blood cell count of 17.6 X 103/ mm3 with 57% of atypical lymphocytes showing convoluted nuclei. A diagnosis of chronic adult Tcell leukemia [3] was made, and thereafter he was kept under medical observation without any treatment. In June 1988, he revisited our hospital with complaints of easy fatigability and low-grade fever. Superficial lymphadenopathy was observed. The peripheral white blood cell count was 102.2 X 103/ mm3 with 69% atypical lymphocytes showing convoluted nuclei, and an elevated lactate dehydrogenase level (2,080 Wrbblewski units [W-U] ) was evident. Surface markers of atypical lymphocytes revealed an inducer/helper phenotype (CD4: 96.4%, CD8: 2.2% and CD4/CD8: 17.5). Myelography showed a nucleated cell count of 25.5 X lOs/mms with 6% atypical lymphocytes. Abdominal echography showed moderate hepatosplenomegaly and a normal-sized pancreas with a smooth surface. A diagnosis of crisis of adult T-cell leukemia [3] was made, and antileukemic chemotherapy (consisting of vincristine, cyclophosphamide, Adriamycin” [doxorubicin], and prednisolone) and supportive therapy were given. This produced a partial remission, and the patient was discharged on September
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1991 The American
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TABLEI Laboratory
Data at Onset of Acute Pancreatitis
Ca hEq/L) P (mEq/L) Amylase (NJ/L) Pancreatic type (%) Trypsin (ng/dL) Lipase (U/L) Elastase-I (ng/dL) WBC (XlOa/mma) ATL cells (%) LDH (W-U) ALP (K-A) Cr (mg/dL) PTH-C (ng/dL) Calcitonin (pg/dL) 6 (%)
Normal Range in Our Hospital
Patient 1
Patient 2
4.5-5.5 1.4-2.6 130-400
6.8 2.5 4,791
5.9 2.5 1,805
140-400 <200 <400
7,7E 1,485 6,600 139 68.5 2,350 22.8 1.7 0.4 232 8.2
9.1:: 1,935 2,830 38
50-400 3-13 0.8-1.5
65: 17.7 1.2 0.2 91 12.0
Ca = serum calcwm; P = serum ~norgamc phosphate, WBC = peripheral white blood cell count; ATL cells = percentage of peripheral adult T-cell leukemrc cell count per white blood cell count: LDH = lactate dehydrogenase: ALP = alkaline phosphatase: Cr = serum creabnme: PTH-C = C-lragment of parathyrold hormone; FEcJ = fractional excretion of calwm: K-A = Krng-Armstrong units.
9, 1988. At this time, swelling of the pancreas was not observed by echography. During the course of the first admission, no elevation of serum amylase or hypercalcemia had been noted. On November 7, 1988, he was readmitted with complaints of anorexia and abdominal discomfort without any history of alcohol-drinking. Until that time, and after his previoys discharge, he had been administered only trimethoprim-sulfamethoxazole for prevention of Pneumocystis carinii infection. On readmission, the blood pressure, regular pulse rate, respiration rate, and body temperature were 154/100 mm Hg, 96 beats/minute, 14/minute, and 36.7”C, respectively. Auscultation of the heart and lungs revealed normal findings. Hepatosplenomegaly and marked jaundice were observed. The kidneys and parathyroid glands were not palpable. There was superficial lymphadenopathy in the cervical, axillary, and inguinal regions. Leg edema and ascites were not present. Laboratory studies on readmission revealed no anemia, an increased peripheral white blood cell count, negative C-reactive protein, and an erythrocyte sedimentation rate of 7 mm/hour. Elevated values of alkaline phosphatase, lactate dehydrogenase, aspartate aminotransferase (455 Karmen units [K-U]), and alanine aminotransferase (342 KU) were found. Serum creatinine was 0.9 mg/dL. Hypercalcemia was not observed at that time. Abdominal echography carried out on November 8 revealed hepatosplenomegaly, swelling of the kidneys, and a smooth and normal-sized pancreas without dilatation of the pancreatic duct or biliary tract. Findings on chest roentgenography and electrocardiography were unremarkable. The patient was treated with glycyrrhizin 80 mg/day intrave252
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nously for the suggestion of post-transfusion hepatitis or drug-induced liver injury. On November 13, the patient suddenly cornplained of severe epigastralgia. However, Koplik’s spots, skin eruption, and swelling of the parotid glands were not found. The levels of serum calcium, pancreatic enzymes, calcitonin, and fractional excretion of calcium were elevated (Table I). Serum inorganic phosphate, serum creatinine, and C-fragment of parathyroid hormone were within normal limits. Hyperlipidemia was not observed. Abdominal echography carried out on November 16 showed an irregular and swollen pancreas without dilatation of the pancreatic duct or presence of stones within the biliary tract. A plain abdominal computed tomographic scan taken immediately after the onset of severe epigastralgia revealed patchy lowdensity areas within the mildly swollen pancreas, no stones within the pancreas or biliary tract, and mild hepatosplenomegaly. The patient was diagnosed as having acute pancreatitis and hypercalcemia in addition to adult Tcell leukemia, and treatment was started for the hypercalcemia with infusion of physiologic saline, prednisolone, and intramuscular calcitonin, for the acute pancreatitis with intravenous nafamostat mesilate and cytidine diphosphate choline, and for the adult T-cell leukemia with antileukemic chemotherapy. Although the levels of serum pancreatic enzymes and calcium and the peripheral white blood cell count were almost normalized by the aforementioned treatments, he died of gastrointestinal bleeding and hepatic failure on January 14, 1989. Laboratory data examined 1 month after the onset of acute pancreatitis showed no elevation of serum antibody titers against hepatitis A, hepatitis B, measles, rubella, Coxsackie B group, ECHO, or Epstein-Barr virus. Gross findings at autopsy included necrosis of the pancreas with fibrosis, hemorrhagic duodenal ulcer, mild splenomegaly, and slightly atrophic liver, while the biliary tract was unremarkable. Postmortem cholangiopancreatography revealed only a slight change in pancreatic duct caliber, and normal passage without stones. The biliary tract was intact, Histologically, fibrosis and infiltration of adult Tcell leukemic cells in the pancreas (Figure I), metastatic calculi within the renal tubules, and submassive necrosis of the liver were observed. Lymph nodes in the hepatic hilus revealed remarkable infiltration of adult T-cell leukemic cells, while bone marrow infiltration was mild. Patient 2
A 38-year-old Japanese woman, born in Nishiuwa-gun, Ehime prefecture, was admitted to Yawatahama City General Hospital on June 6, 90
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Figure 1. Histologic appearance of autopsy specimen of the pancreas from Patient 1. Fibrosis and inspissated secretions in dilated pancreatic ducts are evident in A. Slight infiltration of adult T-cell leukemic cells is apparent in 6. (Hematoxylin and eosin stain: original magnification of A, X106, reduced by 50%; original magnification of B. X424, reduced by 50%.)
1988, with complaints of epigastralgia and acute nausea of 3 days’ duration. She had a history of diffuse panbronchiolitis since the age of 34 years and smoldering adult T-cell leukemia [3] since the age of 37 years. There was no history of hypercalcemia, alcohol-drinking, drug abuse, or smoking. On admission, her blood pressure, regular pulse rate, respiration rate, and body temperature were 114184 mm Hg, 96 beats/minute, 24/minute, and 36.1°C, respectively. Moist rales and piping were audible in the bilateral lung fields. Auscultation of the heart revealed normal findings. Hepatosplenomegaly was observed. The kidneys were not palpable, nor were the superficial lymph nodes or parathyroid glands. Massive ascites were found, together with leg edema. Skin eruption and swelling of the parotid glands were not found. Laboratory studies on admission revealed no anemia, increased peripheral white blood cell count, positive C-reactive protein, and an erythrocyte sedimentation rate of 1 mm/hour. Arterial blood gas analysis revealed pH 7.4, oxygen tension 62.8 mm Hg, and base excess -1.6 mEq/L. Mild hypoproteinemia (6.0 g/dL) and elevated alkaline phosphatase as well as lactate dehydrogenase were seen. M peak was not evident on electrophoresis of serum. Elevated levels of pancreatic enzymes, pancreatic secretory trypsin inhibitor, serum calcium, calcitonin, and fractional excretion of calcium were seen (Table I). Inorganic phosphate, serum creatinine, and C-fragment of parathyroid hormone were all within normal limits. Hyperlipidemia was mild. Serum antibody to adult T-cell leukemia virus-associated antigen was positive. Elevated serum antibody to CD4 (91.1%) and CD4/CD8 ratio (16.6) and decreased serum antibody to CD8 (5.5%) were found. Lymphocyte stimulation tests with phytohemagglutinin and concanavalin-A revealed low values. Antibody titers examined 10 days after the onset of abdominal symptoms, including those against mumps, rubella, Coxsackie B group virus, and mycoplasma, were all negative. Myelography showed a nucleated cell count of 175 X 103/mm3 with 0.4% atypical lymphocytes and 0.2% plasma cells. Leukemic cells with convoluted nuclei were found in the
ascites. Parasitic and bacterial cultures of the stools were negative. Chest roentgenography on admission revealed a bilateral reticulonodular pattern, right pleural effusion, and an elevated diaphragm due to ascites. The electrocardiogram was normal. Abdominal echography showed severe hepatosplenomegaly, swelling of the pancreas with a macular echo pattern, and a smoothly dilated pancreatic duct (3 mm in diameter). No stones were found within the pancreas or biliary tract despite extensive observation. A plain abdominal computed tomographic scan at the time of admission revealed swelling of the pancreas with fluid accumulation, but no stones within the biliary tract. Although diagnosed as having acute pancreatitis and hypercalcemia due to adult T-cell leukemia, the patient refused antileukemic therapy. Therefore, she was treated for hypercalcemia and acute pancreatitis. She died of respiratory and acute renal failure on June 15. Autopsy was not allowed. COMMENTS Clinically, the present two patients fulfilled the diagnostic criteria for adult T-cell leukemia [2,5] and showed obviously associated acute pancreatitis and hypercalcemia on the basis of biochemical and morphologic findings. Many causes of acute pancreatitis have been reported, including biliary tract disease, alcoholdrinking, predominant hyperlipidemia, drugs, certain infections such as those due to viruses, pancreatic tumor, and hypercalcemia [4]. In Patient 1, hypercalcemia, adult T-cell leukemia, and drugs were considered to be possible causes of acute pancreatitis. Among the drugs that were administered to the patient, only prednisolone could have caused this. However, hypercalcemia is usually not associated with prednisolone-induced pancreatitis [6]. Thus, the contribution of prednisolone can almost certainly be ruled out. In Patient 2, hypercalcemia and adult T-cell leukemia were the likely causes of acute pancreatitis. As to the mutual relationship between hypercalcemia and adult T-cell leukemia, the former seems to have been due to the latter, since disorders that
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cause hypercalcemia, such as hyperparathyroidism, myeloma, hypocalciuric hypercalcemia, vitamin D toxicity, and malignancy other than adult T-cell leukemia, were absent. Although there is a high frequency of hypercalcemia associated with adult Tcell leukemia (40% in male patients and 16% in female patients) [7], acute pancreatitis due to hypercalcemia has not been reported as a complication. This is the first report of such a condition. In regard to the etiology of hypercalcemia in adult T-cell leukemia, parathyroid hormone and prostaglandin E have been reported to be within normal limits [8], and instead humoral factors that activate osteoclasts and are produced by adult Tcell leukemic cells have been reported recently [9121. In the present two patients, at least the level of serum parathyroid hormone was within the normal range, and the serum calcitonin level was high among the hormones measured that were related to regulation of the serum calcium level. With reference to the causes of acute pancreatitis due to hypercalcemia, some hypotheses have been proposed from studies of hyperparathyroidism [1315]: these include (1) precipitation of calcium and formation of calculi in the pancreatic ducts, causing ductal obstruction and, secondarily, acinar damage; (2) a direct effect of hypercalcemia, producing damage of pancreatic cells; (3) embolic or thrombotic vascular damage associated with hypercalcemia; (4) conversion of inactive trypsinogen to active trypsin within the pancreas, by virtue of an increased concentration of ionized calcium. In the present two patients, which of the foregoing hypotheses applied is uncertain, because no histologic findings were obtained in the acute phase of pancreatitis. Although the main factor associated with acute pancreatitis was thought to be hypercalcemia in these patients, the contribution of adult T-cell leukemic cell infiltration into the pancreas found at autopsy in Patient 1 could not be ruled out. However, its influence was thought to be slight, since this feature has received little mention in relation to acute pancreatitis in previously reported autopsy studies [16IS], although pancreatic infiltration of adult T-cell leukemic cells was found in 31.3% of autopsy subjects [16]. As to the treatment of this condition, Patient 2, who was treated for acute pancreatitis and hypercalcemia, but not for adult T-cell leukemia, had a poor prognosis. On the other hand, Patient 1 had an improved prognosis following treatment for adult T-cell leukemia as well as acute pancreatitis and hypercalcemia. Thus, for treatment of acute pancreatitis due to hypercalcemia complicating adult
1. Takatsuki K. Uchiyama T. Sagawa K. Yodoi J. Surface markers of malignant lymphoid cells rn the classification of lymphoprokferabve disorders, with spectal reference to adult T-cell leukemia. Jpn J Clin Hematol 1976; 17: 416-21. 2. Uchiyama T. Yodoi J. Sagawa K. Takatsuki K. Uchino H. Adult T-cell leukemia: clinical and hematologic features of 16 cases. Blood 1977: 50: 481-92. 3. Takatsuki K. Adult T-cell leukemia/lymphoma (AIL). Jpn J Med 1984: 23: al3. 4. Lott JA. Inflammatory diseases of the pancreas. CRC Crit Rev Clin Lab Sci 1982; 17: 201-28. 5. Hanaoka M. Progress in adult T-cell leukemia research. Acta Pathol Jpn 1982; 32 (Suppl): 171-85. 6. Mallory A, Kern F. Drug-induced pancreatibs: a cribcal review. Gastroenterology 1980; 78: 813-20. 7. The T- and B-Cell Malignancy Study Group. Statistical analysis of immunologic, clinical and hrstopathologtc data on lymphoid malignancies in Japan. Jpn J Clin Oncol 1981; 11: 15-38. 8. Kiyokawa T. Yamaguchi K. Takeya M. et al. Hypercalcemra and osteoclast proliferatton in adult T-cell leukemia. Cancer 1987: 59: 1187-91. 9. Reichel H. Koeffler HP, Norman AW. 25Hydroxyvitamin Da metabolism by human T-lymphotrophic virus-transformed lymphocytes. J Clin Endocrrnol Metab 1987; 65: 519-26. 10. Shirakawa F. Yamashita U. Tanaka Y. ef al. Production of bone-resorbing activity corresponding to interleukin-ln by adult T-cell leukemia cells in humans. Cancer Res 1988: 48: 4284-7. 11. Wano Y. Hattori T. Matsuoka M. eta/. Interleukin-1 gene expression in adult T-cell leukemia. J Clin Invest 1987: 80: 91 l-6. 12. Niitsu Y. Urushizaki Y. Koshida Y. ef al. Expression of TGF-,9 gene in adult Tcell leukemia. Blood 1988; 71: 263-6. 13. Kelly TR. Relationship of hyperparathyroidism to pancreatitis. Arch Surg 1968; 98: 26714. 14. Baer L. Neu HC. Intravascular clotting and acute pancreatibs in primary hyperparathyroidism. Ann Intern Med 1966: 5: 1062-5. 15. Ludwig GD. Chaykin LB. Pancreatitis associated with primary hyperparathy roidism. Med Clin North Am 1966: 50: 1403-18. 16. Eiichi S. Hasui K. Tokunaga M. Autopsy findings of adult T cell lymphomaleukemia. GANN Monogr Cancer Res 1982; 28: 51-64. 17. Sato E. Tokunaga M. Hasui K. Pathology of non-Hodgkin’s lymphoma in Kagoshima prefecture. with special reference to adult T cell lymphoma. Jpn J Clin Hematol 1979; 20: 1070-82. 18. Haratake J. Horie A, Oda S. eta/. A clinicopathological review of 12 autopsied cases of adult T-cell leukemia. Acta Pathol Jpn 1986: 36: 349-62. 19. Matsumoto M. Nomura K. MatsumotoT. eta/. Adult T-cell leukemia-lymphoma in Kagoshima district. southwestern Japan: clinical and hematological characteristics. Jpn J Clin Oncol 1979: 9 (Suppl): 325-36.
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T-cell leukemia, normalization of the serum calcium level and therapy for acute pancreatitis only are considered insufficient from our experience with a few patients. For improved prognosis, chemotherapy for adult T-cell leukemia is also thought to be necessary from a clinical and biochemical viewpoint. Although a high frequency of abdominal symptoms and infiltration of leukemic cells into the gastrointestinal tract have been reported in adult Tcell leukemia [16,19], the contribution of acute pancreatitis is not clear. More extensive studies on acute pancreatitis associated with hypercalcemia due to adult T-cell leukemia should help to clarify the incidence and relationship of abdominal symptoms and also the prognosis.
REFERENCES
CASE REPORTS
Two Cases of Adult T-Cell Leukemia Associated with Acute Pancreatitis due to Hypercalcemia YASUNOBU DAZAI, M.D., ICHIJIRO KATOH, M.D., YUJI HARA, M.D., RYOICHI YOSHIDA, M.D., Yawatahama, Japan, KENJI KURIHARA, M.D., Uwajima, Japan
We report two cases of adult T-cell leukemia associated with acute pancreatitis and hypercalcemia. After sudden onset of epigastralgia, acute pancreatitis and hypercalcemia were found in both patients. There were no diseases that could explain the acute pancreatitis except for hypercalcemia probably due to adult T-cell leukemia. Thus we considered that hypercalcemia due to adult T-cell leukemia had led to acute pancreatitis. This is the first report of such a complication in adult T-cell leukemia.
From the Department of Internal Medicine (YD. IK. YH, RY). Yawatahama City General Hospital. Yawatahama, Japan, and the Depariment of Pathology (KK), Uwaiima Municipal Hospital, Uwajima. Japan. Requests for reprints should be addressed to Yasunobu Dazai, M.D., Department of Internal Medicine, Yawatahama City General Hospital, Oohira. Yawatahama, Ehime 796, Japan. Manuscript submitted March 15. 1990. and accepted in revised form July 12. 1990.
dult T-cell leukemia is a human T-cell leukemia virus type I-associated leukemia endemic in southern Japan and the Caribbean basin [l-3]. It has several characteristics including convoluted Tlymphocyte nuclei, positive antibody to adult T-cell leukemia virus-associated antigen, and a high frequency of hypercalcemia. As to hypercalcemia as one of the causes of acute pancreatitis [4], there has been no report of acute pancreatitis caused by hypercalcemia due to adult T-cell leukemia. Here we report two cases of adult T-cell leukemia associated with acute pancreatitis due to hypercalcemia.
A
CASEREPORTS Patient 1 A 39-year-old Japanese man, born in Yawatahama City, Ehime prefecture, presented to Yawatahama City General Hospital in May 1988 with a complaint of tinea unguium. He had no history of previous illness, drug abuse, or blood transfusion. His peripheral blood revealed positivity for serum antibody to adult T-cell leukemia virus-associated antigen and a white blood cell count of 17.6 X 103/ mm3 with 57% of atypical lymphocytes showing convoluted nuclei. A diagnosis of chronic adult Tcell leukemia [3] was made, and thereafter he was kept under medical observation without any treatment. In June 1988, he revisited our hospital with complaints of easy fatigability and low-grade fever. Superficial lymphadenopathy was observed. The peripheral white blood cell count was 102.2 X 103/ mm3 with 69% atypical lymphocytes showing convoluted nuclei, and an elevated lactate dehydrogenase level (2,080 Wrbblewski units [W-U] ) was evident. Surface markers of atypical lymphocytes revealed an inducer/helper phenotype (CD4: 96.4%, CD8: 2.2% and CD4/CD8: 17.5). Myelography showed a nucleated cell count of 25.5 X lOs/mms with 6% atypical lymphocytes. Abdominal echography showed moderate hepatosplenomegaly and a normal-sized pancreas with a smooth surface. A diagnosis of crisis of adult T-cell leukemia [3] was made, and antileukemic chemotherapy (consisting of vincristine, cyclophosphamide, Adriamycin” [doxorubicin], and prednisolone) and supportive therapy were given. This produced a partial remission, and the patient was discharged on September
February
1991 The American
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Volume
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251
A RARE COMPLICATION
OF ATL / DAZAI ET AL
TABLEI Laboratory
Data at Onset of Acute Pancreatitis
Ca hEq/L) P (mEq/L) Amylase (NJ/L) Pancreatic type (%) Trypsin (ng/dL) Lipase (U/L) Elastase-I (ng/dL) WBC (XlOa/mma) ATL cells (%) LDH (W-U) ALP (K-A) Cr (mg/dL) PTH-C (ng/dL) Calcitonin (pg/dL) 6 (%)
Normal Range in Our Hospital
Patient 1
Patient 2
4.5-5.5 1.4-2.6 130-400
6.8 2.5 4,791
5.9 2.5 1,805
140-400 <200 <400
7,7E 1,485 6,600 139 68.5 2,350 22.8 1.7 0.4 232 8.2
9.1:: 1,935 2,830 38
50-400 3-13 0.8-1.5
65: 17.7 1.2 0.2 91 12.0
Ca = serum calcwm; P = serum ~norgamc phosphate, WBC = peripheral white blood cell count; ATL cells = percentage of peripheral adult T-cell leukemrc cell count per white blood cell count: LDH = lactate dehydrogenase: ALP = alkaline phosphatase: Cr = serum creabnme: PTH-C = C-lragment of parathyrold hormone; FEcJ = fractional excretion of calwm: K-A = Krng-Armstrong units.
9, 1988. At this time, swelling of the pancreas was not observed by echography. During the course of the first admission, no elevation of serum amylase or hypercalcemia had been noted. On November 7, 1988, he was readmitted with complaints of anorexia and abdominal discomfort without any history of alcohol-drinking. Until that time, and after his previoys discharge, he had been administered only trimethoprim-sulfamethoxazole for prevention of Pneumocystis carinii infection. On readmission, the blood pressure, regular pulse rate, respiration rate, and body temperature were 154/100 mm Hg, 96 beats/minute, 14/minute, and 36.7”C, respectively. Auscultation of the heart and lungs revealed normal findings. Hepatosplenomegaly and marked jaundice were observed. The kidneys and parathyroid glands were not palpable. There was superficial lymphadenopathy in the cervical, axillary, and inguinal regions. Leg edema and ascites were not present. Laboratory studies on readmission revealed no anemia, an increased peripheral white blood cell count, negative C-reactive protein, and an erythrocyte sedimentation rate of 7 mm/hour. Elevated values of alkaline phosphatase, lactate dehydrogenase, aspartate aminotransferase (455 Karmen units [K-U]), and alanine aminotransferase (342 KU) were found. Serum creatinine was 0.9 mg/dL. Hypercalcemia was not observed at that time. Abdominal echography carried out on November 8 revealed hepatosplenomegaly, swelling of the kidneys, and a smooth and normal-sized pancreas without dilatation of the pancreatic duct or biliary tract. Findings on chest roentgenography and electrocardiography were unremarkable. The patient was treated with glycyrrhizin 80 mg/day intrave252
February
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nously for the suggestion of post-transfusion hepatitis or drug-induced liver injury. On November 13, the patient suddenly cornplained of severe epigastralgia. However, Koplik’s spots, skin eruption, and swelling of the parotid glands were not found. The levels of serum calcium, pancreatic enzymes, calcitonin, and fractional excretion of calcium were elevated (Table I). Serum inorganic phosphate, serum creatinine, and C-fragment of parathyroid hormone were within normal limits. Hyperlipidemia was not observed. Abdominal echography carried out on November 16 showed an irregular and swollen pancreas without dilatation of the pancreatic duct or presence of stones within the biliary tract. A plain abdominal computed tomographic scan taken immediately after the onset of severe epigastralgia revealed patchy lowdensity areas within the mildly swollen pancreas, no stones within the pancreas or biliary tract, and mild hepatosplenomegaly. The patient was diagnosed as having acute pancreatitis and hypercalcemia in addition to adult Tcell leukemia, and treatment was started for the hypercalcemia with infusion of physiologic saline, prednisolone, and intramuscular calcitonin, for the acute pancreatitis with intravenous nafamostat mesilate and cytidine diphosphate choline, and for the adult T-cell leukemia with antileukemic chemotherapy. Although the levels of serum pancreatic enzymes and calcium and the peripheral white blood cell count were almost normalized by the aforementioned treatments, he died of gastrointestinal bleeding and hepatic failure on January 14, 1989. Laboratory data examined 1 month after the onset of acute pancreatitis showed no elevation of serum antibody titers against hepatitis A, hepatitis B, measles, rubella, Coxsackie B group, ECHO, or Epstein-Barr virus. Gross findings at autopsy included necrosis of the pancreas with fibrosis, hemorrhagic duodenal ulcer, mild splenomegaly, and slightly atrophic liver, while the biliary tract was unremarkable. Postmortem cholangiopancreatography revealed only a slight change in pancreatic duct caliber, and normal passage without stones. The biliary tract was intact, Histologically, fibrosis and infiltration of adult Tcell leukemic cells in the pancreas (Figure I), metastatic calculi within the renal tubules, and submassive necrosis of the liver were observed. Lymph nodes in the hepatic hilus revealed remarkable infiltration of adult T-cell leukemic cells, while bone marrow infiltration was mild. Patient 2
A 38-year-old Japanese woman, born in Nishiuwa-gun, Ehime prefecture, was admitted to Yawatahama City General Hospital on June 6, 90
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Figure 1. Histologic appearance of autopsy specimen of the pancreas from Patient 1. Fibrosis and inspissated secretions in dilated pancreatic ducts are evident in A. Slight infiltration of adult T-cell leukemic cells is apparent in 6. (Hematoxylin and eosin stain: original magnification of A, X106, reduced by 50%; original magnification of B. X424, reduced by 50%.)
1988, with complaints of epigastralgia and acute nausea of 3 days’ duration. She had a history of diffuse panbronchiolitis since the age of 34 years and smoldering adult T-cell leukemia [3] since the age of 37 years. There was no history of hypercalcemia, alcohol-drinking, drug abuse, or smoking. On admission, her blood pressure, regular pulse rate, respiration rate, and body temperature were 114184 mm Hg, 96 beats/minute, 24/minute, and 36.1°C, respectively. Moist rales and piping were audible in the bilateral lung fields. Auscultation of the heart revealed normal findings. Hepatosplenomegaly was observed. The kidneys were not palpable, nor were the superficial lymph nodes or parathyroid glands. Massive ascites were found, together with leg edema. Skin eruption and swelling of the parotid glands were not found. Laboratory studies on admission revealed no anemia, increased peripheral white blood cell count, positive C-reactive protein, and an erythrocyte sedimentation rate of 1 mm/hour. Arterial blood gas analysis revealed pH 7.4, oxygen tension 62.8 mm Hg, and base excess -1.6 mEq/L. Mild hypoproteinemia (6.0 g/dL) and elevated alkaline phosphatase as well as lactate dehydrogenase were seen. M peak was not evident on electrophoresis of serum. Elevated levels of pancreatic enzymes, pancreatic secretory trypsin inhibitor, serum calcium, calcitonin, and fractional excretion of calcium were seen (Table I). Inorganic phosphate, serum creatinine, and C-fragment of parathyroid hormone were all within normal limits. Hyperlipidemia was mild. Serum antibody to adult T-cell leukemia virus-associated antigen was positive. Elevated serum antibody to CD4 (91.1%) and CD4/CD8 ratio (16.6) and decreased serum antibody to CD8 (5.5%) were found. Lymphocyte stimulation tests with phytohemagglutinin and concanavalin-A revealed low values. Antibody titers examined 10 days after the onset of abdominal symptoms, including those against mumps, rubella, Coxsackie B group virus, and mycoplasma, were all negative. Myelography showed a nucleated cell count of 175 X 103/mm3 with 0.4% atypical lymphocytes and 0.2% plasma cells. Leukemic cells with convoluted nuclei were found in the
ascites. Parasitic and bacterial cultures of the stools were negative. Chest roentgenography on admission revealed a bilateral reticulonodular pattern, right pleural effusion, and an elevated diaphragm due to ascites. The electrocardiogram was normal. Abdominal echography showed severe hepatosplenomegaly, swelling of the pancreas with a macular echo pattern, and a smoothly dilated pancreatic duct (3 mm in diameter). No stones were found within the pancreas or biliary tract despite extensive observation. A plain abdominal computed tomographic scan at the time of admission revealed swelling of the pancreas with fluid accumulation, but no stones within the biliary tract. Although diagnosed as having acute pancreatitis and hypercalcemia due to adult T-cell leukemia, the patient refused antileukemic therapy. Therefore, she was treated for hypercalcemia and acute pancreatitis. She died of respiratory and acute renal failure on June 15. Autopsy was not allowed. COMMENTS Clinically, the present two patients fulfilled the diagnostic criteria for adult T-cell leukemia [2,5] and showed obviously associated acute pancreatitis and hypercalcemia on the basis of biochemical and morphologic findings. Many causes of acute pancreatitis have been reported, including biliary tract disease, alcoholdrinking, predominant hyperlipidemia, drugs, certain infections such as those due to viruses, pancreatic tumor, and hypercalcemia [4]. In Patient 1, hypercalcemia, adult T-cell leukemia, and drugs were considered to be possible causes of acute pancreatitis. Among the drugs that were administered to the patient, only prednisolone could have caused this. However, hypercalcemia is usually not associated with prednisolone-induced pancreatitis [6]. Thus, the contribution of prednisolone can almost certainly be ruled out. In Patient 2, hypercalcemia and adult T-cell leukemia were the likely causes of acute pancreatitis. As to the mutual relationship between hypercalcemia and adult T-cell leukemia, the former seems to have been due to the latter, since disorders that
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1991 The American
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cause hypercalcemia, such as hyperparathyroidism, myeloma, hypocalciuric hypercalcemia, vitamin D toxicity, and malignancy other than adult T-cell leukemia, were absent. Although there is a high frequency of hypercalcemia associated with adult Tcell leukemia (40% in male patients and 16% in female patients) [7], acute pancreatitis due to hypercalcemia has not been reported as a complication. This is the first report of such a condition. In regard to the etiology of hypercalcemia in adult T-cell leukemia, parathyroid hormone and prostaglandin E have been reported to be within normal limits [8], and instead humoral factors that activate osteoclasts and are produced by adult Tcell leukemic cells have been reported recently [9121. In the present two patients, at least the level of serum parathyroid hormone was within the normal range, and the serum calcitonin level was high among the hormones measured that were related to regulation of the serum calcium level. With reference to the causes of acute pancreatitis due to hypercalcemia, some hypotheses have been proposed from studies of hyperparathyroidism [1315]: these include (1) precipitation of calcium and formation of calculi in the pancreatic ducts, causing ductal obstruction and, secondarily, acinar damage; (2) a direct effect of hypercalcemia, producing damage of pancreatic cells; (3) embolic or thrombotic vascular damage associated with hypercalcemia; (4) conversion of inactive trypsinogen to active trypsin within the pancreas, by virtue of an increased concentration of ionized calcium. In the present two patients, which of the foregoing hypotheses applied is uncertain, because no histologic findings were obtained in the acute phase of pancreatitis. Although the main factor associated with acute pancreatitis was thought to be hypercalcemia in these patients, the contribution of adult T-cell leukemic cell infiltration into the pancreas found at autopsy in Patient 1 could not be ruled out. However, its influence was thought to be slight, since this feature has received little mention in relation to acute pancreatitis in previously reported autopsy studies [16IS], although pancreatic infiltration of adult T-cell leukemic cells was found in 31.3% of autopsy subjects [16]. As to the treatment of this condition, Patient 2, who was treated for acute pancreatitis and hypercalcemia, but not for adult T-cell leukemia, had a poor prognosis. On the other hand, Patient 1 had an improved prognosis following treatment for adult T-cell leukemia as well as acute pancreatitis and hypercalcemia. Thus, for treatment of acute pancreatitis due to hypercalcemia complicating adult
1. Takatsuki K. Uchiyama T. Sagawa K. Yodoi J. Surface markers of malignant lymphoid cells rn the classification of lymphoprokferabve disorders, with spectal reference to adult T-cell leukemia. Jpn J Clin Hematol 1976; 17: 416-21. 2. Uchiyama T. Yodoi J. Sagawa K. Takatsuki K. Uchino H. Adult T-cell leukemia: clinical and hematologic features of 16 cases. Blood 1977: 50: 481-92. 3. Takatsuki K. Adult T-cell leukemia/lymphoma (AIL). Jpn J Med 1984: 23: al3. 4. Lott JA. Inflammatory diseases of the pancreas. CRC Crit Rev Clin Lab Sci 1982; 17: 201-28. 5. Hanaoka M. Progress in adult T-cell leukemia research. Acta Pathol Jpn 1982; 32 (Suppl): 171-85. 6. Mallory A, Kern F. Drug-induced pancreatibs: a cribcal review. Gastroenterology 1980; 78: 813-20. 7. The T- and B-Cell Malignancy Study Group. Statistical analysis of immunologic, clinical and hrstopathologtc data on lymphoid malignancies in Japan. Jpn J Clin Oncol 1981; 11: 15-38. 8. Kiyokawa T. Yamaguchi K. Takeya M. et al. Hypercalcemra and osteoclast proliferatton in adult T-cell leukemia. Cancer 1987: 59: 1187-91. 9. Reichel H. Koeffler HP, Norman AW. 25Hydroxyvitamin Da metabolism by human T-lymphotrophic virus-transformed lymphocytes. J Clin Endocrrnol Metab 1987; 65: 519-26. 10. Shirakawa F. Yamashita U. Tanaka Y. ef al. Production of bone-resorbing activity corresponding to interleukin-ln by adult T-cell leukemia cells in humans. Cancer Res 1988: 48: 4284-7. 11. Wano Y. Hattori T. Matsuoka M. eta/. Interleukin-1 gene expression in adult T-cell leukemia. J Clin Invest 1987: 80: 91 l-6. 12. Niitsu Y. Urushizaki Y. Koshida Y. ef al. Expression of TGF-,9 gene in adult Tcell leukemia. Blood 1988; 71: 263-6. 13. Kelly TR. Relationship of hyperparathyroidism to pancreatitis. Arch Surg 1968; 98: 26714. 14. Baer L. Neu HC. Intravascular clotting and acute pancreatibs in primary hyperparathyroidism. Ann Intern Med 1966: 5: 1062-5. 15. Ludwig GD. Chaykin LB. Pancreatitis associated with primary hyperparathy roidism. Med Clin North Am 1966: 50: 1403-18. 16. Eiichi S. Hasui K. Tokunaga M. Autopsy findings of adult T cell lymphomaleukemia. GANN Monogr Cancer Res 1982; 28: 51-64. 17. Sato E. Tokunaga M. Hasui K. Pathology of non-Hodgkin’s lymphoma in Kagoshima prefecture. with special reference to adult T cell lymphoma. Jpn J Clin Hematol 1979; 20: 1070-82. 18. Haratake J. Horie A, Oda S. eta/. A clinicopathological review of 12 autopsied cases of adult T-cell leukemia. Acta Pathol Jpn 1986: 36: 349-62. 19. Matsumoto M. Nomura K. MatsumotoT. eta/. Adult T-cell leukemia-lymphoma in Kagoshima district. southwestern Japan: clinical and hematological characteristics. Jpn J Clin Oncol 1979: 9 (Suppl): 325-36.
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T-cell leukemia, normalization of the serum calcium level and therapy for acute pancreatitis only are considered insufficient from our experience with a few patients. For improved prognosis, chemotherapy for adult T-cell leukemia is also thought to be necessary from a clinical and biochemical viewpoint. Although a high frequency of abdominal symptoms and infiltration of leukemic cells into the gastrointestinal tract have been reported in adult Tcell leukemia [16,19], the contribution of acute pancreatitis is not clear. More extensive studies on acute pancreatitis associated with hypercalcemia due to adult T-cell leukemia should help to clarify the incidence and relationship of abdominal symptoms and also the prognosis.
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