MICROANGIOPATHIC HEMOLYTIC ANEMIA IN CARCINOMA OF THE STOMACH

GASTROENTEROLOGY Copyright 1967 by The Williams & Wilkins Co. Vol. 52, No.1 Printed in U.S.A. MICROANGIOPATHIC HEMOLYTIC ANEMIA IN CARCINOMA OF THE STOMACH EDWARD C. LYNCH, M.D., CURTIS L. BAKKEN, M.D., THOMAS H. CASEY, M.D AND CLARENCE P. ALFREY, JR., M.D. Departments of Medicine and Pathology, St. Luke's Episcopal Hospital and Baylor University College of Medicine, Houston, Texas Anemia occurs frequently in patients with disseminated carcinoma of the stomach. Common causes are acute gastrointestinal hemorrhage, iron deficiency, and the anemia of malignancy.1-3 Occasionally, the anemia may be megaloblastic,t, 4, 5 autoimmune hemolytic,6 or myelophthisic. 6-8 In 1962, Brain et ai.9 described in 5 patients with widespread malignancy an unusual anemia in which severe hemolysis was associated with pathological changes in small blood vessels. Termed "microangiopathic hemolytic anemia," the disorder was characterized by striking morphological changes in the erythrocytes. In the case reported here, these distinctive erythrocytic abnormalities led to the diagnosis of microangiopathic hemolytic anemia and allowed the premortem prediction of the extensive vascular involvement by gastric carcinoma later found at necropsy. Case Report A 47-year-old Caucasian electrician was admitted to the hospital on January 16, 1966, because of back pain. In October 1962, with the preoperative radiographic diagnosis of duodenal ulcer, the patient underwent subtotal gastrectomy because of upper gastrointestinal hemorrhage. The resected stomach contained a penetrating, nonperforating ulcer, 2.3 cm in diameter, at the gastroduodenal junction. Microscopic ex- Received July 6, 1966. Accepted August 1, 1966. Address requests for reprints to: Dr. Edward C. Lynch, Department of Hematology, Methodist Hospital, Texas Medical Center, Houston, Texas 77025. This investigation was supported by Research Grant HE-09252-02, Project No.1, from the National Institutes of Health, Bethesda, Maryland. 88 amination disclosed gastric mucosa on the proximal margin and duodenal mucosa on the distal margin of the ulcer (fig. 1). In addition to the usual histopathological changes of a peptic ulcer, a focus of moderately well differentiated, mucin-producing adenocarcinoma (0.5 em in diameter) was identified in the gastric margin of the ulcer. The tumor had invaded one small area of the submucosa. After the operation, hematemesis and melena were never again noted, but occasional mild postprandial epigastric discomfort occurred. During the year before his final hospitalization, the patient experienced easy fatigability, mild anorexia, a loss of weight of 10 pounds, and minimal exertional dyspnea. Eight weeks before admission, pain developed in both scapular areas and in the thoracic spine. Shortly thereafter, a steady pain appeared in the upper lumbar area, leading to hospitalization. Examination revealed a thin, pale man with no jaundice. A hard mass, extrinsic to the rectum, was felt in the cul-de-sac. Movements of the lumbar spine were moderately limited. Palpation over the upper lumbar vertebrae elicited mild tenderness. No other significant physical abnormalities were detected. The hemoglobin was 5.7 g per 100 ml, hematocrit, 19.5%, and the corrected white blood cell count, 9250 per mm 3 The differential count revealed 53% segmented neutrophils, 15% bands, 1 % metamyelocytes, 6% myelocytes, 1% myeloblasts, 1% eosinophils, 1% basophils, and 22% lymphocytes. There were 19 normoblasts per 100 white blood cells. Platelets numbered 30,000 per mm 3 Reticulocytes constituted 30% of the red blood cells. A smear of the peripheral blood revealed marked anisocytosis and poikilocytosis, a significantly increased number of polychromatophilic erythrocytes, many schistocytes and helmet cells, numerous contracted spherocytes, occasional tear drop red blood cells, and a few erythrocytes with coarse basophilic stippling

January 1967 CASE REPORTS 89 FIG. 1 (upper left). Histological section of resected ulcer at gastroduodenal junction. Note tumor cells at gastric margin of ulcer (X 125). FIG. 2 (upper right). Smear of peripheral blood illustrating marked anisocytosis and poikilocytosis, spherocytes and schistocytes ( X 525). FIG. 3 (lower). Arteriole of lung filled with mucin-producing adenocarcinoma cells (X 312). (fig. 2). Smears of the buffy coat of the peripheral blood disclosed numerous normoblasts and immature myeloid cells and occasional megakaryocytes and tumor cells. The direct Coombs' reaction was negative. Serum iron was 240 f.lg per 100 ml. The Venereal Disease Research Laboratory sample was nonreactive; fasting blood sugar, 100 mg per 100 ml; blood urea nitrogen, 15 mg per 100 ml ; serum calcium, 10 mg per 100 ml; alkaline phosphatase, 3.5 Bessey-Lowrey units; glutamic-oxaloacetic transaminase, 36 units; glutamic-pyruvic transaminase, 8 units; and plasma prothrombin activity, 53% of normal. Three specimens of stool gave a negative guaiac reaction. Roentgenographic studies revealed a heart of normal size, enlarged hilar shadows, and metastatic lesions in the seventh to tenth thoracic vertebrae and the first and second lumbar vertebrae. Radiographic visualization of the upper gastrointestinal tract showed a subtotal gastrectomy without evidence of recurrent malignancy in the stomach. Three constricting lesions of the colon were discovered by barium enema examination. Aspiration and biopsy of iliac crest bone marrow with a Vim-Silverman needle on the sixth hospital day disclosed more than 60% of the nucleated cells to be large tumor cells, each with several nucleoli. Megakaryocytes, erythroid precursors, and granulocytic precursors were few in number. Review of sections of the marrow clot and the biopsy specimen revealed a poorly differentiated, mucinproducing adenocarcinoma. On the ninth hospital day following the transfusion of four units of blood, the hemoglobin was 6.2 g per 100 ml and the hematocrit, 19%. No blood loss was observed during the course of the hospitalization except for mild epistaxis on the 10th hospital day. The patient developed a severe headache early on the 11th hospital day, lapsed into coma, and died several hours later. At necropsy, a poorly differentiated, mucinproducing adenocarcinoma extensively infiltrated the hilar, retroperitoneal and mesenteric

90 CASE REPORTS Vol. 52, No.1 lymph nodes, the adrenal glands, the sternum, lumbar, and thoracic vertebrae, and the serosa, muscularis externa, and submucosa of the gastrointestinal tract ~ n urinary d bladder. The gastroduodenal anastomosis showed no evidence of recurrent tumor. Although no hepatic metastases were observed grossly, microscopic examination revealed adenocarcinoma cells in the periportal areas. Histological examination disclosed that numerous pulmonary arteries and arterioles were distended with poorly differentiated, mucin-producing malignant cells (fig. 3). Many of the periarterial and peribronchial lymphatics also contained tumor. Intravascular tumor emboli were demonstrable only in the lungs. A subarachnoid hemorrhage was present over the right cerebral hemisphere, cerebellum, and brain stem. There was no microscopic evidence of intracranial tumor. Discussion The reticulocytosis of 30% without demonstrable blood loss indicated that the severe anemia in this patient was principally hemolytic. Two types of hemolytic anemia, autoimmune and microangiopathic, have been described in patients with carcinoma. Autoimmune hemolytic anemia is confirmed by the demonstration of a positive Coombs' reaction and has been described in patients with carcinoma arising in the stomach,6 colon,lo breast,!l and cervix. 12 The negative Coombs' reaction in our patient during the period of severe hemolysis essentially excluded autoimmunity as the mechanism of the hemolytic process. Microangiopathic hemolytic anemia has been observed in a variety of diseases that have in common pathological changes in the smaller arteries and arterioles. Among these disorders are thrombotic thrombocytopenia purpura,9. 13. 14 malignant hypertension,9. 15 renal cortical necrosis,d. H. 16 acute glomerulonephritis,9. 14 polyarteritis nodosa,d systemic lupus erythematosus,9 and disseminated carcinoma.ḍ 17. IS In patients with carcinoma who have manifested this type of anemia, the tumor has originated in the stomach,9 lung,9 breast,17 and prostate. 9 In 1 case, postmortem examination failed to reveal the primary site of the tumor. 1S Although there are only 3 previously recorded cases of gastric carcinoma in which the diagnosis of microangiopathic hemolytic anemia was made,9 there are several other reports concerning patients with cancer of the stomach and severe hemolysis, in whom, in retrospect, this diagnosis was likely.19-23 The morphological changes of the erythrocytes in patients with microangiopathic hemolytic anemia consist of striking anisocytosis and poikilocytosis, the presence of schistocytes (small irregularly shaped red cell fragments), helmet cells (triangular erythrocytes), burr cells, microspherocytes, and a marked increase in polychromatophilic erythrocytes. 9. 24 These erythrocytic abnormalities, commonly referred to as the erythrocyte fragmentation syndrome, have also been observed in patients with hemolytic anemia associated with artificial cardiac valves,25-2s Teflon patch repairs of ostium primum defects 29-31 and atrioventriculare commune,si and aortic stenosis. 32 - ss Two types of histological changes have been associated with microangiopathic hemolytic anemia in patients with disseminated carcinoma-intravascular hyaline thrombi 9 and vascular involvement by tumor aggregates. Ḍ IS The present case represented a striking example of the latter abnormality, since extensive intravascular invasion by malignant cells was observed in the lungs at postmortem examination. A similar case with substantial intravascular pulmonary involvement has been reported. 1s Although the mechanism by which the intravascular tumor emboli induce hemolysis has not been defined, a mechanical basis seens reasonable. Hemolysis could result from turbulence generated by the obstructing tumor aggregates. More attractive, however, is the concept that hemolysis occurs by direct interaction and/ or collision of erythrocytes with a foreign surface. The foreign surface is the tumor cell in cases of malignancy, the pathologically altered intima 24 in patients with diffuse small vessel diseases, and the nonendothelialized Teflon patch 29. 30 in patients with repaired endocardial cushion

January 1967 CASE REPORTS 91 defects. Interestingly, subsequent endothelialization of Teflon grafts may result in diminution of hemolysis. 29, 30 Landaw 34 suggested a nonmechanical explanation for the hemolytic anemias of carcinoma. N oting that most subjects with carcinoma and hemolytic anemia have a mucin-producing adenocarcinoma arising from the gastrointestinal tract, he hypothesized that a product of these tumors, such as "colloid", "mucin," or "pseudomucin," is responsible for the hemolysis. Significant thrombocytopenia was observed in the present case. This is not surprising in view of the common occurrence of thrombocytopenia in the various disorders accompanied by microangiopathic hemolytic anemia.9, 13, 17 Brain et a1.9 reported thrombocytopenia in their 3 cases of gastric carcinoma with microangiopathic hemolytic anemia. It has been proposed that the thrombocytopenia results from hyperutilization of platelets in association with intravascular thrombosis.24 In addition to the hemolysis, our patient's hematological status was affected by a myelophthisic process reflected by the presence of many normoblasts, immature granulocytes, and megakaryocytes in the peripheral blood. Tumor cells were demonstrated in the marrow during life by aspiration and biopsy. Extensive involvement of the marrow by carcinoma was confirmed by necropsy. Although mild to moderate reticulocytosis may occur in myelophthisic anemia, we attribute the marked reticulocytosis of the present case to the erythropoietic response to hemolysis, since a reticulocyte percentage above 7.1 is unusual in myelophthisic anemias.35,36 Thirty years ago, J archo 37 described a special group of patients with diffusely infiltrating carcinoma of the stomach, who had a number of features in common. Onehalf of these patients were below the age of 40. The primary gastric tumor was small, frequently located in or near the pylorus, and scirrhous or diffusely infiltrating. Metastases were generally infiltrating in type, rather than nodular. Hepatic metastases were uncommon, but Krukenberg tumor of the ovary was frequent. Lymphatic involvement of the lungs and diffuse intravascular involvement by the tumor were common. These patients often had severe anemia, thrombocytopenia, and a leukoerythroblastic picture of the peripheral blood. Necropsy disclosed extensive involvement of the bone marrow. Our patient, as well as a number of reported cases of hemolytic anemia in carcinoma of the stomach,19-21, 23 had many findings similar to J archo's patients. Thus it seems appropriate to add microangiopathic hemolytic anemia to the list of abnormalities that characterize disseminated, diffusely infiltrating adenocarcinoma of the stomach. Summary A patient with disseminated carcinoma of the stomach is described in whom severe hemolytic anemia occurred in association with the morphological changes of the erythrocyte fragmentation syndrome. The anemia was of the microangiopathic hemolytic type and reflected the extensive pulmonary vascular involvement by malignant emboli found at necropsy. Recognition of these erythrocytic abnormalities-schistocytes, helmet cells, spherocytes, and polychromatophilic red blood cells-in patients with gastric cancer and hemolytic anemia should prompt the clinician to suspect strongly the presence of intravascular tumor emboli. REFERENCES 1. Ley, A. B. 1956. Mechanisms of anemia III cancer. Med. Clin. N. Amer. 40: 857-870. 2. Hyman, G. A., and J. E. Harvey. 1955. The pathogenesis of anemia in patients with carcinoma. Amer. J. Med. 19: 350-356. 3. Miller, A., R. B. Chodos, C. P. Emerson, and J. F. Ross. 1956. Studies of the anemia and iron metabolism in cancer. J. Clin. Invest. 35: 1248-1262. 4. MacLean, L. D., and R. D. Sundberg. 1956. Incidence of megaloblastic anemia after total gastrectomy. New Eng. J. Med. 254: 885-893. 5. MacLean, L. D. 1957. Incidence of megaloblastic anemia after subtotal gastrectomy. New Eng. J. Med. 257: 262-265.

92 CASE REPORTS Vol. 52, No.1 6. Frumin, A. M., T. H. Mendell, and D. R. Merange. 1954. Hematologic manifestations of metastatic gastric malignancy. Gastroenterology 27: 183-188. 7. Mettier, S. R. 1940. Hematologic aspects of space consuming lesions of the bone marrow (myelophthisic anemia). Ann. Intern. Med. 14: 436-448. 8. Case Records of the Massachusetts General Hospital. Case 21-1963. New Eng. J. Med. 268: 672-678. 9. Brain, M. C., J. V. Dacie, and D. O'B. Hourihane. 1962. Microangiopathic haemolytic anemia; the possible role of vascular lesions m pathogenesis. Brit. J. Haemat. 8: 358-374. 10. Stats, D., N. Rosenthal, and L. R. Wasserman. 1947. Hemolytic anemia associated with malignant diseases. Amer. J. Clin. Path. 17: 585-613. 11. Sohier, W. D., Jr., E. Juranies, and J. C. Aub. 1957. Hemolytic anemia, a host response to malignancy. Cancer Res. 17: 767-774. 12. Ellis, L. D., and M. P. Westerman. 1965. Autoimmune hemolytic anemia and cancer. J. A. M. A. 193: 962-964. 13. Adelson, E., E. J. Heitzman, and J. F. Fennessey. 1954. Thrombohemolytic thrombocytopenic purpura. A. M. A. Arch. Intern. Med. 94: 42-60. 14. McQuiggan, M. C., W. J. Oliver, E. R. Littler, and J. C. Cerny. 1965. Hemolytic uremic syndrome. J. A. M. A. 191: 787-792. 15. Capelli, J. P., L. G. Wesson, and A. V. Erslev. 1966. Malignant hypertension and red cell fragmentation syndrome. Ann. Intern. Med. 64: 128-136. 16. Gasser, C., E. Gautier, A. Steck, R. E. Siebenmann, and R. Oeschlin. 1955. Hamolytisch-uramische Syndrome: bilaterale Nierenrindennekrosen bei akuten erworbenen hamolytischen Anamien. Schweiz. Med. Wschr. 85: 905-909. 17. Stratford, E. C., and K. R. Tanaka. 1965. Microangiopathic hemolytic anemia in metastatic carcinoma. Report of a case and biochemical studies. Arch. Intern. Med. (Chicago) 116: 346-350. 18. Clinicopathologic Conference. 1965. Congenital hemolytic jaundice corrected by splenectomy followed twenty-six years later by bleeding tendency, hepatomegaly and sudden death. Amer. J. Med. 38: 257-267. 19. Seemann, G., and A. Krasnopolski. 1926. Akute "Leukanamie" mit starker extramedullarer Blutbildung als Folge ausgedehnter Knochenmarksverdrangung durch Magenkrebsmetastasen. Virchow. Arch. Path. Anat. 262: 697-711. 20. Terplan, K., and S. L. Vaughan. 1934. Primary carcinoma of the stomach-grossly unrecognizable-with extensive metastases to the bone marrow producing marked intravital erythroblastosis. Arch. Path. 18: 924-925. 21. Holmes, J. MacD., and A. J. McCall. 1940. Jaundice in leucoerythroblastic anaemia. Brit. Med. J. 2: 698-700. 22. Hogeman, O. 1953. Hyperhemolysis of nonsplenic origin. Acta Med. Scand. 144: 247-262. 23. Case Records of the Massachusetts General Hospital. Case 57-1962. New Eng. J. Med. 267: 452-460. 24. Dacie, J. V. 1963. Hemolyse et troubles vasculaires. Nouv. Rev. Franc. Hemat. 3: 205-208. 25. Stevenson, T. D., and H. J. Baker. 1964. Haemolytic anaemia following insertion of Starr-Edwards valve prosthesis. Lancet 2: 982-985. 26. Marsh, G. W. 1964. Intravascular haemolytic anaemia after aortic-valve replacement. Lancet 2: 986-988. 27. DeCesare, W., C. Rath, and C. Hufnagel. 1965. Hemolytic anemia of mechanical origin with aortic-valve prosthesis. New Eng. J. Med. 272: 1045-1050. 28. Petz, L. D., and J. R. Goodman. 1966. Ringed sideroblasts and intramitochondrial iron in cases of mechanical hemolytic anemia. Significance of these findings and observations on the etiology of hemolysis. Ann. Intern. Med. 64: 635-643. 29. Sayed, H. M., J. V. Dacie, D. A. Handley, S. M. Lewis, and W. P. Cleland. 1961. Haemolytic anaemia of mechanical origin after open heart surgery. Thorax 16: 356-360. 30. Verdon, T. A., Jr., R. H. Forrester, and W. H. Crosby. 1963. Hemolytic anemia after openheart repair of ostium-primum defects. New Eng. J. Med. 269: 444-446. 31. Sigler, A. T., E. N. Forman, W. H. Zinkham, and C. Neill. 1963. Severe intravascular hemolysis following surgical repair of endocardial cushion defects. Amer. J. Med. 35: 467-480. 32. Case Records of the Massachusetts General Hospital. Case 52-1964. New Eng. J. Med. 271: 898-905. 33. Brodeur, M. T. H., D. W. Sutherland, R. D. Koler, J. A. Kimsey, and H. E. Griswold. 1964. Red cell survival in patients with"

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