JOURNAL OF THE AMERICAN GERIATRICS SOCIETY Copyright © 1975 by the American Geriatrics Society
Vol. XXIII. No.9 Printed in U.S.A.
Metastatic Hemangioperieytoma Associated with Microangiopathic Hemolytic Anemia: Review and Report of a Case EDWARD C. KUPERS, MD*, NATHAN B. FRIEDMAN, MD, STEPHEN LEE, MD and RALPH S. WOLFSTEIN, MD The Department of Internal Medicine, the Department of Pathology and the Department of Nuclear Medicine of Cedars of Lebanon Hospital Division, Cedars Sinai Medical Center, Los Angeles, California ABSTRACT: The hemanglopericytoma is an invasive tumor of vascular origin. No matter how benign the course and how circumscribed the mass, it must be considered a lesion with high malignant potential. In the case reported here, a hemangiopericytoma of the pancreas with metastasis to the liver was associated with mieroangiopathic hemolytic anemia in a 78-year old woman. The anemia may have been present before the onset of metastasis. If so, it could have been a major factor in the breakdown of host response and could have initiated the malignant dissemination. Under these circumstances it could be an indicator of metastasis in patients with previously diagnosed tumors. However, there are many cases of metastatic malignancy associated with this anemia in which the opposite situation holds. The anemia is usually of extracorpuscular origin. Apparently intravascular coagulation caused by injury from tumor-cell aggregates in small vessels induces erythrocyte fragmentation on fibrin strands. A vicious cycle of cell fragmentation, vascular injury and fibrin strand formation completes the course. Analysis of the findings should be based upon more than a strictly pathologic approach; it should also be related to the new discoveries in cancer research.
The combination of metastatic malignancy and microangiopathic hemolytic anemia is found in various anatomic and pathologic settings. The present report describes the first known case of malignant hemangiopericytoma associated with this type of hemolytic anemia. CASE REPORT The patient, a 78-year-old woman of Spanish origin, was admitted to Cedars of Lebanon Hospitalon July 19, 1973 for evaluation of a huge mass in the left upper quadrant of the abdomen and a concomitant Coombs' -negative hemolytic anemia. The anemia dated back to at least 1968. At that * Address:
5255 Sunset Boulevard. Los Angeles. CA 90027.
411
time the patient was examined because of vaginal bleeding. Uterine dilatation and curettage gave negative results. The bone marrow showed "normal erythropoiesis, normal leukopoiesis, normal megakaryocytes, normal stainable iron in the marrow, and no evidence of a granulomatous or neoplastic process." In February 1973, the hemoglobin level suddenly dropped from 13.7 gm to 8.8 gm/100 ml. The entire progression of the anemia occurred within twelve days without overt signs of bleeding. This precipitated another hematologic work-up. Three stool examinations did not reveal any occult blood. The report on blood smears stated: "There are a number of abnormalities including some macrocytosis and polychromasia, but the minority of the cells are large, most being normocytic. There is no obvious hypochromia. Erythrocyte
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morphology is otherwise hard to assess . The leukocytes are present in normal numbers, but there are some premyelocytes . In addition, there is some hypersegmentation of the polys with a number of four-segment polys, several five-segment polys and one six-segment poly. Platelets are adequate. Impression: Anemia, probably normochromic; etiology undetermined." During the hospital admission in February 1973, physical examinations by interns, residents, attending instructors, the attending physician, and surgical and hematology consultants failed to detect any palpable mass in the left upper quadrant of the abdomen, and no x-ray reports described such a mass. However, only a few months later, in July 1973, the findings were quite different. A large mass, 25 x 30 em, well circumscribed and movable, was easily palpable in the left upper quadrant. It felt cystic and was not tender. Immediately below and apparently attached to this cystic tumor was a more solid mass; a souffle was audible over both . There were no cutaneous signs of inflammation or erythema . The liver was palpable three fingerbreadths below the costal margin, and the tip of the spleen was barely palpable. The kidneys could not be felt. The skin was free of jaundice or rash . In February 1973, the peripheral blood findings were as follows: hemoglobin level 8.8 gm/100 ml, hematocrit 26.6 per cent, leukocyte count 9500/cu mm , mean corpuscular hemoglobin count 34.4 per cent, mean corpuscular volume 105 cu IJ-, and mean corpuscular hemoglobin 36.31J- IJ-g. Erythrocytes were normochromic with moderate anisocytosis and poikilocytosis. Occasional macrocytes, fragmented erythrocytes and burr cells were seen. There was moderate polychromasia. Leukocytes
A
.1"'\
showed a left shift to myelocytes in the granulocytic series, and a few atypical lymphocytes were present. Platelets were normal ; reticulocytes 8 per cent. Serum iron concentration and iron binding capacity were low. Coombs' test and the hemolysis test gave negative results; there was no free plasma hemoglobin. Several stool examinations did not show an y occult blood. The levels of electrophoretic proteins were normal , but haptoglobins were slightly below normal. Normal val ues were obtained for serum transaminase (SGOT, SGPT), lactic dehydrogenase, creatine phosphokinase, glucose-6 -P dehydrogenase, and for the Murphy-Pattee and triiodothyronine tests. The serum sodium level was 135 mg/100 ml, potassium 3.1 mg/lOO ml, chloride 98 mg/lOO ml and carbon dioxide 27 mEq/liter. Leucine aminopeptidase activity was normal. Serum amylase, lipase and urine amylase values were normal. Tests for prothrombin, partial thromboplastin time and Factor viii gave normal results. Several months later, during the hospital ad mission of July 1973, progressive changes were observed. The erythrocytes (wet-mount preparation) showed a poikilocytosis of 3 +, mostly burr cells. Many misshapen forms , fragments and microspherocytes were seen (Fig. 1). There was a normochromic anisocytosis of 2 +, with round macrocytes and occasional basophilic stippling. A few ovalocytes, target cells and tear-drop cells were noted. Several hemograms showed: hemoglobin level 8-10 gm/lOO ml; hematocrit 26-28 per cent; erythrocyte count 3,000,000/cu mm; leukocyte count and differential count normal; platelet count 200,000-225,000/cu mm with normal morphology; reticulocytes 3.5 per cent and reticulocyte count 98,500/cu mm. There were no hyper-
"
_
Fig. 1. A. Microangiopathic Hemolytic Anemia. A. Blood smear showing fragmented and other typical erythrocytes. B. (Same patient) Fragmented and distorted erythrocytes. (Wright Giemsa stain. x 125.)
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segmented leukocytes. In two smears, the polymorphonuclear cells were 90 and 84 per cent respectively. No atypical lymphocytes were noted. The blood levels of bilirubin, calcium, phos-
Fig. 2. Anterior and right lateral liver: large defect in left lobe; multiple defects in right lobe.
phorus, urea nitrogen, creatinine, uric acid and cholesterol were within normal limits. Alkaline phosphatase activity was only slightly elevated. The VDRL test for syphilis gave negative results. A liver scan (Fig. 2) showed mottled distribution of sulfur-colloid and several areas of decreased activity described as " suggest ing metastatic involvement." A large filling defect in the left upper quadrant appeared to compress or replace the left lobe of the liver and extend into the left lower quadrant of the abdomen. It seemed to be extrinsic to the liver, but an anterior blood flow study was suggested for verification. Blood flow in the abdominal aorta was grossly abnormal (Fig. 3) with evidence of a vascular mass in the area of the left lobe of the liver overlying the upper part of an avascular larger mass, both corresponding exactly with the palpable mass in the same area. The spleen was minimally enlarged. No filling defects were noted. Sulfur-colloid activity was not increased in the spleen or in the bone marrow . A pancreas scan (Fig. 4) showed gross abnormalities. A large cystic mass replaced most of the pancreatic body and tail. An area of concentration contiguous to the pancreatic head and below the normal position of the body seemed to be intrinsic. A large area of concentration (less than background) in the left mid-abdomen was correlated with the large palpable masses, and the
Fig. 3. Abdominal perfusion study. Aorta displaced to right . Early abnormal blush on left showing a rim of blood flow around a very large area of low concentration, in the medial portion of which is a large area of abnormal increase. Immediate static image shows scalloped appearance of per ipheral increase surrounding an area of concentration less than normal vascular background, within which is a large area of abnormal increase.
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Fig. 4. Pancreas scan (above) with and without subtraction technique, plus liver scan (below) for direct comparison. Marked distortion of pancreas. Abnormally increased concentration of selenimethionine, quite extensive at med ial aspect of functioning liver. A large area of concentration, less than normal vascular background, at the left lateral aspect. Impression: Very large cyst ic but vascular neoplasm within either the liver or pancreas or extrinsic thereto, but distorting both organs. Additional liver metastases are present.
area next to the liver (Fig. 4) showed normal background concentration - further eivdence of an additional non-cystic abnormality. X-ray examination of the gastrointestinal tract revealed a large mass that filled almost the entire left side of the abdomen, with obliteration of the psoas shadow. There was marked compression of the body of the stomach, which was displaced medially and anteriorly by the mass. Infusion nephrotomograms showed "the presence of a very large soft tissue mass in the left upper and middle abdomen which is displacing the kidney posteriorly. " At operation, a huge retrogastric mass was found which occupied the entire left upper quadrant of the abdomen and extended to the left lower quadrant. The mass was multicystic, but there were several firm areas . It originated in the pancreas and involved the retroperitoneum. The liver was the seat of multiple metastatic deposits. A biopsy specimen was taken from the right lobe of the liver. Gross pathologic description : "Labelled liver biopsy specimen is a wedge of soft tissue. Along one surface is a strip of tan liver. Beneath that is a translucent white tumor mass that has a uniform fme grained surface." Microscopic description (Fig. 5, A-E) : "Liver contains a metastatic nodule of tumor composed of neoplastic pericytes. The tumor cells are ir-
414
regularly rounded, with an abundant clear cytoplasm. The mildly pleomorphic nuclei contain irregular nucleoli. Mitotic activity is rare. The tumor cells are arranged in vague packets around capillary spaces, mostly collapsed. Some cystic dilatation of the vascular spaces is noted. Diagnosis : Metastatic hemangiopericytoma, liver." DISCUSSION The foregoing case constitutes additional evidence that metastatic malignancy is often associated with microangiopathic hemolytic anemia . The findings are consistent with the growing impression that no matter how benign the course and how circumscribed the tumor mass, any hemangiopericytoma is potentially invasive and highly malignant. The vascular origin of this type of tumor accounts for its ubiquitous occurrence and also for the great variety of behavior patterns. In 1942, Stout and Murray (1) described the hemangiopericytoma as a vascular tumor composed of capillaries surrounded by elongated con tractile cells resembling Zimmermann's peri cytes. The abnormal cells are extraluminal. The tumors are deceptive; they appear benign, but in fact they are biologically aggressive. O'Brien and Brasfield (2) reported 24 cases and concluded that these tumors "are highly malignant over a life-
September 1975
METASTATIC HEMANGIOPERICYTOMA + HEMOLYTIC ANEMIA
Fig. 5. A. Tumor, liver, and fibrous capsular separation. The tumor cells are generally spindle shaped or fusiform with thicker midportions and thinner pointed ends. In places they are almost epithelioid. They are grouped in long trabeculae which appear as perithelial clumps in cross section. (Hematoxylin-eosin, reduced from x 168.) B. Perithelial and alveolar groupings of tumor cells. The rosette-like clusters surround small vascular spaces and some areas have small alveolar groups of neoplastic elements. The small cavities are the result of cellular breakdown, and some spaces show a dilated central vessel. (Masson trichrome, reduced from x420.) C. Higher power view of B (reduced from x675). Argyrophile reticulum surrounds individual cells from the endothelial channels. Mitoses are rare. (Fig. 5 continued on next page.)
time but not in a five year concept." Metastases frequently occur after many years of inactivity and the tumors may spread locally or through the bloodstream and lymphatics. There are two prerequisites for the diagnosis of hemangiopericytoma: 1) endothelial cells must retain their normal appearance and be separated from pericytes by a fibrous sheath, and 2) the proliferating tumor cell must be a pericyte. These tumors have been reported in patients of all age groups. Hemangiopericytomas usually are painless, unless pain is caused by pressure on other tissues. There is no predilection for either sex. The locations ofthe tumors in recorded cases have been the muscles, retroperitoneum, omentum,
orbit, tongue, nasal cavity, pericardium, diaphragm, ileum, bone, meninges, uterus, skin and subcutaneous tissues (6-19). The histologic appearance often fails to indicate whether the tumor is malignant or benign; even the ultramicroscopic appearance is not conclusive (3, 4). In 1956, Stout (5) pointed out that tumors in the retroperitoneum and mediastinum show a relatively high incidence of metastases, whereas small superficial tumors are unlikely to spread. As long as a hemangiopericytoma does not metastasize, the hematologic status of the patient remains unremarkable. However, as with various other metastatic malignant tumors when the continuity of the vascular endothelium is de-
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Fig. 5. D. Tumor cells outside of reticulum which demarcates vascular channels. The fibrous capsule demarcating tumor tissue from hepatic parenchyma is breached at several points with tumor growing into the liver substance. (Gomori reticulum. x675.l E. Reticulum surrounding cellular groups and individual tumor elements (Gomori reticulum. x675.l
stroyed by intravascular aggregates of tumor cells and the metastatic damage results in fibrin precipitation and platelet adherence, the stage is set for an acute destructive hematologic complication. The erythrocytes circulating through the newly diseased small blood vessels undergo an increase in shearing stress. Fragmentation occurs, and disseminated intravascular coagulation usually results. Increased platelet consumption causes thrombocytopenia. The process continues as a vicious cycle. The direct destruction of erythrocytes on the surface of intravascular tumor cells, added to fragmentation as the cells pass through the fibrin strands, is further enhanced by
416
the release of thrombokinase-like, coagulationpromoting substances directly into the blood (20). The fragmented cells assume many different shapes, e.g., helmet cells, contracted cells, triangular cells, burr cells, crenated cells, and various erythrocyte fragments. The combination of this schistocytosis with microspherocytosis, reticulocytosis, and an anemia chiefly extracorpuscular in origin, acute in onset and rapid in progression, satisfies the criteria for the diagnosis of microangiopathic hemolytic anemia, so well described by Brain, Dacie and Hourihane (21) in 1962. The association of this hematologic complication with benign tumors has not been recorded.
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In the case presented here, a metastasizing hemangiopericytoma of the pancreas and retroperitoneum had extensively invaded the liver and other organs and had somehow become associated with a microangiopathic hemolytic anemia. One must think beyond the facts. We do not know the origin of the anemia. We cannot be certain of which came first, the anemia or the metastasis. The initiating factors of this type of extracorpuscular hemolytic anemia in a setting of vascular injury are still a matter of conjecture. What is the actual pathomechanism of this fatal combination of pathologic lesions? It is possible that tumor cell aggregates initiated the disruption of the integrity and continuity of vascular endothelium. It is also possible that the vicious cycle of fibrin precipitation, platelet aggregation, erythrocyte fragmentation, chemical releases from ruptured cells and an extracorpuscular hemolytic anemia and thrombocytopenia resulted therefrom. But we have no adequate proof. If there is a common denominator for metastasis and anemia in these cases, it is probably related to the defense mechanism of the host. This patient may have been manufacturing cancer cells for many years. It could be that for some reason she lost the humoral substances and antibodies that were keeping her safe by destroying the malignant cells as they formed. Perhaps blocking antibodies were present, but this would not be the only way. A fibrinolysis or microangiopathic hemolysis could be at fault. The breakdown of a total host response might embody many things. Genetically changed cells, tumor specificity of antigens and humoral substances, loss of antigens, genetic changes on the surface of cells, variable effects of viral infection, misdirected immunologic responses, abnormal B cells or T cells and immune globulin disturbances-any or all of these are possible factors in a breakdown of host resistance.. Ever since Ewing established the histogenetic classification of tumor cells in 1919, the pathologist has been the arbiter of most of the issues in cancer. In the present case, as in most cases of malignancy today, the pathologist's contribution is becoming only a portion of the pie. A hemangiopericytoma which was relatively dormant for many years and so small that it was clinically undetectable only a few months before its rapid spread, must have undergone some major alteration unknown to us. Was this due to genetic changes (22), antigenic changes or alterations in host response? Viruses can cause leukemia
(23-25). But if a virus was the etiologic factor in our patient, why wasn't the malignancy in the form of leukemia? In this case, a breakdown in host response appears to be the most logical hypothesis. Whether or not there is a common pathway for this and other metastatic malignant lesions, the present state of our knowledge limits us in making an appraisal. We can only depend on the contributions of research to date. But rather than the strictly pathologic view, we should be thinking also in terms of immunologic surveillance, cytogenetics, biochemistry (e.g., defective aerobic glycolysis), endocrine disturbances and other approaches. The initiating factor of the extracorpuscular hemolytic anemia in this woman may have been aggregates of tumor cells, but it is also possible that the anemia and not the tumor cells set things in motion by some elusive mechanism which researchers may soon discover. In the near future it may even be possible to use detection of microangiopathic hemolytic anemia in a patient with a previously diagnosed tumor as an indication that metastatic disease has developed (20, 26-30). REFERENCES 1. Stout AP and Murray MR: Hemangiopericytoma; a vascular tumor featuring Zimmermann's pericytes, Ann Surg 116: 26, 1942. 2. O'Brien P and Brasfield RD: Hemangiopericytoma, Cancer 18: 249, 1965. 3. Fernando NVP and Movat HZ: The fine structure of the terminal vascular bed. III. The capillaries, Exper Molec Path 3: 87, 1964. 4. Movat HZ and Fernando NVP: The fine structure of the terminal vascular bed. IV. The venules and their perivascular cells, Exper Molec Path 3: 98, 1964. 5. Stout AP: Tumors featuring pericytes; glomus tumor and hemangiopericytoma, Lab Invest 5: 217, 1956. 6. Hakala TR, Page D and Fleischli DJ: Paravesical hemangiopericytoma, J Urol 103: 436, 1970. 7. Greene RR, Gerbie AB and Eckman TR: Hernangiopericytomas of the uterus, Am JObst Gynec 106: 1020, 1970. 8. Backwinkel KD and Diddams JA: Hemangiopericytoma; report of a case and comprehensive review of the literature, Cancer 25: 896, 1970. 9. Ayella RJ: Hemangiopericytoma; a case report with arteriographic findings, Radiology 97: 611, 1970. 10. Hahn MJ, Dawson R, Esterly JA et al: Hemangiopericytoma; an ultrastructural study, Cancer 31: 255, 1973. 11. Sugar HS, Fishman GR, Kobernick S et al: Orbital hemangiopericytoma or vascular meningioma, Am J. Ophthalmol 70: 103, 1970. 12. Gurney N, Chalkley T and O'Grady R: Lacrimal sac hemangiopericytoma, Am J Ophthalmol 71: 757, 1971. 13. Reymond RD, Hazra TA and Edlow DW: Hernangiopericytoma of the vulva with metastasis to bone 14 years later, Brit J Radiol 45: 765, 1972.
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KUPERS ET AL. 14. Silverberg SG, Willson MA and Board JA: Hemangiopericytoma of the uterus: an ultrastructural study, Am J Obst & Gynec 110: 397, 1971. 15. Lambert MB and Daw E: Hemangiopericytoma of the uterus, Practitioner 210: 255, 1973. 16. Kirshen EJ, Naftolin F and Benirschke K: Uterine hemangiopericytoma in a 19-year-old woman, Obst Gynec 40: 652, 1972. 17. Shugart RR: Glomus tumors and hemangiopericytomas of the extremities and trunk. Thesis, Graduate School, University of Minnesota, 1961. 18. Harrison HC and Bulteau V: Hemangiopericytoma of the nasal cavity, Aust NZ J Surg 41: 251, 1972. 19. Alii AF and Singh SP: Hemangiopericytoma in the nasal cavity in Ibadan, Nigeria, J Laryngol 86: 405, 1972. 20. Lohrman HP, Wolfgang A and Heymer B: Microangiopathic hemolytic anemia in metastatic carcinoma; report of eight cases, Ann Int Med 79: 368, 1973. 21. Brain MC, Dacie JV and Hourihane DO: Microangiopathic hemolytic anemia: the possible role of vascular lesions in pathogenesis, Brit J. Haemat 8: 358, 1962. 22. Sandberg AA and Hossfeld DK: Chromosomal abnormalities in human neoplasia, Ann Rev. Med 21: 379, 1970.
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23. M.D. Anderson Hospital & Tumor Institute: Carcinogenesis: A Broad Critique. Baltimore, Williams & Wilkins, 1967. 24. Holland JF and Frei E: Cancer Medicine. Philadelphia, Lea & Febiger, 1973. 25. M.D. Anderson Hospital & Tumor Institute: The Proliferation and Spread of Neoplastic Cells. Baltimore, Williams & Wilkins, 1968. 26. Brain MC: Microangiopathic hemolytic anemia, Ann Rev Med 21: 133, 1970. 27. Joseph RR, Day HJ, Sherwin RM et al: Microangiopathic hemolytic anemia associated with consumption coagulopathy in a patient with disseminated carcinoma, Scandinar J Hematol 4: 271, 1967. 28. Levin H: Microangiopathic hemolytic anemia: the pathogenesis of red blood cell fragmentation; a review of the literature, Aerospace Med 41: 331, 1970. 29. Tapp E and Ralston A: Thrombotic microangiopathy associated with squamous carcinoma, Brit Med J 4: 209, 1969. 30. Bull BS and Kuhn IN: The production of schistocytes by fibrin strands (a scanning electron microscope study), Blood 35: 104, 1970.
Vol. XXIII. No.9 Printed in U.S.A.
Metastatic Hemangioperieytoma Associated with Microangiopathic Hemolytic Anemia: Review and Report of a Case EDWARD C. KUPERS, MD*, NATHAN B. FRIEDMAN, MD, STEPHEN LEE, MD and RALPH S. WOLFSTEIN, MD The Department of Internal Medicine, the Department of Pathology and the Department of Nuclear Medicine of Cedars of Lebanon Hospital Division, Cedars Sinai Medical Center, Los Angeles, California ABSTRACT: The hemanglopericytoma is an invasive tumor of vascular origin. No matter how benign the course and how circumscribed the mass, it must be considered a lesion with high malignant potential. In the case reported here, a hemangiopericytoma of the pancreas with metastasis to the liver was associated with mieroangiopathic hemolytic anemia in a 78-year old woman. The anemia may have been present before the onset of metastasis. If so, it could have been a major factor in the breakdown of host response and could have initiated the malignant dissemination. Under these circumstances it could be an indicator of metastasis in patients with previously diagnosed tumors. However, there are many cases of metastatic malignancy associated with this anemia in which the opposite situation holds. The anemia is usually of extracorpuscular origin. Apparently intravascular coagulation caused by injury from tumor-cell aggregates in small vessels induces erythrocyte fragmentation on fibrin strands. A vicious cycle of cell fragmentation, vascular injury and fibrin strand formation completes the course. Analysis of the findings should be based upon more than a strictly pathologic approach; it should also be related to the new discoveries in cancer research.
The combination of metastatic malignancy and microangiopathic hemolytic anemia is found in various anatomic and pathologic settings. The present report describes the first known case of malignant hemangiopericytoma associated with this type of hemolytic anemia. CASE REPORT The patient, a 78-year-old woman of Spanish origin, was admitted to Cedars of Lebanon Hospitalon July 19, 1973 for evaluation of a huge mass in the left upper quadrant of the abdomen and a concomitant Coombs' -negative hemolytic anemia. The anemia dated back to at least 1968. At that * Address:
5255 Sunset Boulevard. Los Angeles. CA 90027.
411
time the patient was examined because of vaginal bleeding. Uterine dilatation and curettage gave negative results. The bone marrow showed "normal erythropoiesis, normal leukopoiesis, normal megakaryocytes, normal stainable iron in the marrow, and no evidence of a granulomatous or neoplastic process." In February 1973, the hemoglobin level suddenly dropped from 13.7 gm to 8.8 gm/100 ml. The entire progression of the anemia occurred within twelve days without overt signs of bleeding. This precipitated another hematologic work-up. Three stool examinations did not reveal any occult blood. The report on blood smears stated: "There are a number of abnormalities including some macrocytosis and polychromasia, but the minority of the cells are large, most being normocytic. There is no obvious hypochromia. Erythrocyte
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KUPERS ET AL.
morphology is otherwise hard to assess . The leukocytes are present in normal numbers, but there are some premyelocytes . In addition, there is some hypersegmentation of the polys with a number of four-segment polys, several five-segment polys and one six-segment poly. Platelets are adequate. Impression: Anemia, probably normochromic; etiology undetermined." During the hospital admission in February 1973, physical examinations by interns, residents, attending instructors, the attending physician, and surgical and hematology consultants failed to detect any palpable mass in the left upper quadrant of the abdomen, and no x-ray reports described such a mass. However, only a few months later, in July 1973, the findings were quite different. A large mass, 25 x 30 em, well circumscribed and movable, was easily palpable in the left upper quadrant. It felt cystic and was not tender. Immediately below and apparently attached to this cystic tumor was a more solid mass; a souffle was audible over both . There were no cutaneous signs of inflammation or erythema . The liver was palpable three fingerbreadths below the costal margin, and the tip of the spleen was barely palpable. The kidneys could not be felt. The skin was free of jaundice or rash . In February 1973, the peripheral blood findings were as follows: hemoglobin level 8.8 gm/100 ml, hematocrit 26.6 per cent, leukocyte count 9500/cu mm , mean corpuscular hemoglobin count 34.4 per cent, mean corpuscular volume 105 cu IJ-, and mean corpuscular hemoglobin 36.31J- IJ-g. Erythrocytes were normochromic with moderate anisocytosis and poikilocytosis. Occasional macrocytes, fragmented erythrocytes and burr cells were seen. There was moderate polychromasia. Leukocytes
A
.1"'\
showed a left shift to myelocytes in the granulocytic series, and a few atypical lymphocytes were present. Platelets were normal ; reticulocytes 8 per cent. Serum iron concentration and iron binding capacity were low. Coombs' test and the hemolysis test gave negative results; there was no free plasma hemoglobin. Several stool examinations did not show an y occult blood. The levels of electrophoretic proteins were normal , but haptoglobins were slightly below normal. Normal val ues were obtained for serum transaminase (SGOT, SGPT), lactic dehydrogenase, creatine phosphokinase, glucose-6 -P dehydrogenase, and for the Murphy-Pattee and triiodothyronine tests. The serum sodium level was 135 mg/100 ml, potassium 3.1 mg/lOO ml, chloride 98 mg/lOO ml and carbon dioxide 27 mEq/liter. Leucine aminopeptidase activity was normal. Serum amylase, lipase and urine amylase values were normal. Tests for prothrombin, partial thromboplastin time and Factor viii gave normal results. Several months later, during the hospital ad mission of July 1973, progressive changes were observed. The erythrocytes (wet-mount preparation) showed a poikilocytosis of 3 +, mostly burr cells. Many misshapen forms , fragments and microspherocytes were seen (Fig. 1). There was a normochromic anisocytosis of 2 +, with round macrocytes and occasional basophilic stippling. A few ovalocytes, target cells and tear-drop cells were noted. Several hemograms showed: hemoglobin level 8-10 gm/lOO ml; hematocrit 26-28 per cent; erythrocyte count 3,000,000/cu mm; leukocyte count and differential count normal; platelet count 200,000-225,000/cu mm with normal morphology; reticulocytes 3.5 per cent and reticulocyte count 98,500/cu mm. There were no hyper-
"
_
Fig. 1. A. Microangiopathic Hemolytic Anemia. A. Blood smear showing fragmented and other typical erythrocytes. B. (Same patient) Fragmented and distorted erythrocytes. (Wright Giemsa stain. x 125.)
412
September 1975
METASTATIC HEMANGIOPERICYTOMA + HEMOLYTIC ANEMIA
segmented leukocytes. In two smears, the polymorphonuclear cells were 90 and 84 per cent respectively. No atypical lymphocytes were noted. The blood levels of bilirubin, calcium, phos-
Fig. 2. Anterior and right lateral liver: large defect in left lobe; multiple defects in right lobe.
phorus, urea nitrogen, creatinine, uric acid and cholesterol were within normal limits. Alkaline phosphatase activity was only slightly elevated. The VDRL test for syphilis gave negative results. A liver scan (Fig. 2) showed mottled distribution of sulfur-colloid and several areas of decreased activity described as " suggest ing metastatic involvement." A large filling defect in the left upper quadrant appeared to compress or replace the left lobe of the liver and extend into the left lower quadrant of the abdomen. It seemed to be extrinsic to the liver, but an anterior blood flow study was suggested for verification. Blood flow in the abdominal aorta was grossly abnormal (Fig. 3) with evidence of a vascular mass in the area of the left lobe of the liver overlying the upper part of an avascular larger mass, both corresponding exactly with the palpable mass in the same area. The spleen was minimally enlarged. No filling defects were noted. Sulfur-colloid activity was not increased in the spleen or in the bone marrow . A pancreas scan (Fig. 4) showed gross abnormalities. A large cystic mass replaced most of the pancreatic body and tail. An area of concentration contiguous to the pancreatic head and below the normal position of the body seemed to be intrinsic. A large area of concentration (less than background) in the left mid-abdomen was correlated with the large palpable masses, and the
Fig. 3. Abdominal perfusion study. Aorta displaced to right . Early abnormal blush on left showing a rim of blood flow around a very large area of low concentration, in the medial portion of which is a large area of abnormal increase. Immediate static image shows scalloped appearance of per ipheral increase surrounding an area of concentration less than normal vascular background, within which is a large area of abnormal increase.
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Vol. XXIII
Fig. 4. Pancreas scan (above) with and without subtraction technique, plus liver scan (below) for direct comparison. Marked distortion of pancreas. Abnormally increased concentration of selenimethionine, quite extensive at med ial aspect of functioning liver. A large area of concentration, less than normal vascular background, at the left lateral aspect. Impression: Very large cyst ic but vascular neoplasm within either the liver or pancreas or extrinsic thereto, but distorting both organs. Additional liver metastases are present.
area next to the liver (Fig. 4) showed normal background concentration - further eivdence of an additional non-cystic abnormality. X-ray examination of the gastrointestinal tract revealed a large mass that filled almost the entire left side of the abdomen, with obliteration of the psoas shadow. There was marked compression of the body of the stomach, which was displaced medially and anteriorly by the mass. Infusion nephrotomograms showed "the presence of a very large soft tissue mass in the left upper and middle abdomen which is displacing the kidney posteriorly. " At operation, a huge retrogastric mass was found which occupied the entire left upper quadrant of the abdomen and extended to the left lower quadrant. The mass was multicystic, but there were several firm areas . It originated in the pancreas and involved the retroperitoneum. The liver was the seat of multiple metastatic deposits. A biopsy specimen was taken from the right lobe of the liver. Gross pathologic description : "Labelled liver biopsy specimen is a wedge of soft tissue. Along one surface is a strip of tan liver. Beneath that is a translucent white tumor mass that has a uniform fme grained surface." Microscopic description (Fig. 5, A-E) : "Liver contains a metastatic nodule of tumor composed of neoplastic pericytes. The tumor cells are ir-
414
regularly rounded, with an abundant clear cytoplasm. The mildly pleomorphic nuclei contain irregular nucleoli. Mitotic activity is rare. The tumor cells are arranged in vague packets around capillary spaces, mostly collapsed. Some cystic dilatation of the vascular spaces is noted. Diagnosis : Metastatic hemangiopericytoma, liver." DISCUSSION The foregoing case constitutes additional evidence that metastatic malignancy is often associated with microangiopathic hemolytic anemia . The findings are consistent with the growing impression that no matter how benign the course and how circumscribed the tumor mass, any hemangiopericytoma is potentially invasive and highly malignant. The vascular origin of this type of tumor accounts for its ubiquitous occurrence and also for the great variety of behavior patterns. In 1942, Stout and Murray (1) described the hemangiopericytoma as a vascular tumor composed of capillaries surrounded by elongated con tractile cells resembling Zimmermann's peri cytes. The abnormal cells are extraluminal. The tumors are deceptive; they appear benign, but in fact they are biologically aggressive. O'Brien and Brasfield (2) reported 24 cases and concluded that these tumors "are highly malignant over a life-
September 1975
METASTATIC HEMANGIOPERICYTOMA + HEMOLYTIC ANEMIA
Fig. 5. A. Tumor, liver, and fibrous capsular separation. The tumor cells are generally spindle shaped or fusiform with thicker midportions and thinner pointed ends. In places they are almost epithelioid. They are grouped in long trabeculae which appear as perithelial clumps in cross section. (Hematoxylin-eosin, reduced from x 168.) B. Perithelial and alveolar groupings of tumor cells. The rosette-like clusters surround small vascular spaces and some areas have small alveolar groups of neoplastic elements. The small cavities are the result of cellular breakdown, and some spaces show a dilated central vessel. (Masson trichrome, reduced from x420.) C. Higher power view of B (reduced from x675). Argyrophile reticulum surrounds individual cells from the endothelial channels. Mitoses are rare. (Fig. 5 continued on next page.)
time but not in a five year concept." Metastases frequently occur after many years of inactivity and the tumors may spread locally or through the bloodstream and lymphatics. There are two prerequisites for the diagnosis of hemangiopericytoma: 1) endothelial cells must retain their normal appearance and be separated from pericytes by a fibrous sheath, and 2) the proliferating tumor cell must be a pericyte. These tumors have been reported in patients of all age groups. Hemangiopericytomas usually are painless, unless pain is caused by pressure on other tissues. There is no predilection for either sex. The locations ofthe tumors in recorded cases have been the muscles, retroperitoneum, omentum,
orbit, tongue, nasal cavity, pericardium, diaphragm, ileum, bone, meninges, uterus, skin and subcutaneous tissues (6-19). The histologic appearance often fails to indicate whether the tumor is malignant or benign; even the ultramicroscopic appearance is not conclusive (3, 4). In 1956, Stout (5) pointed out that tumors in the retroperitoneum and mediastinum show a relatively high incidence of metastases, whereas small superficial tumors are unlikely to spread. As long as a hemangiopericytoma does not metastasize, the hematologic status of the patient remains unremarkable. However, as with various other metastatic malignant tumors when the continuity of the vascular endothelium is de-
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Fig. 5. D. Tumor cells outside of reticulum which demarcates vascular channels. The fibrous capsule demarcating tumor tissue from hepatic parenchyma is breached at several points with tumor growing into the liver substance. (Gomori reticulum. x675.l E. Reticulum surrounding cellular groups and individual tumor elements (Gomori reticulum. x675.l
stroyed by intravascular aggregates of tumor cells and the metastatic damage results in fibrin precipitation and platelet adherence, the stage is set for an acute destructive hematologic complication. The erythrocytes circulating through the newly diseased small blood vessels undergo an increase in shearing stress. Fragmentation occurs, and disseminated intravascular coagulation usually results. Increased platelet consumption causes thrombocytopenia. The process continues as a vicious cycle. The direct destruction of erythrocytes on the surface of intravascular tumor cells, added to fragmentation as the cells pass through the fibrin strands, is further enhanced by
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the release of thrombokinase-like, coagulationpromoting substances directly into the blood (20). The fragmented cells assume many different shapes, e.g., helmet cells, contracted cells, triangular cells, burr cells, crenated cells, and various erythrocyte fragments. The combination of this schistocytosis with microspherocytosis, reticulocytosis, and an anemia chiefly extracorpuscular in origin, acute in onset and rapid in progression, satisfies the criteria for the diagnosis of microangiopathic hemolytic anemia, so well described by Brain, Dacie and Hourihane (21) in 1962. The association of this hematologic complication with benign tumors has not been recorded.
September 1975
METASTATIC HEMANGIOPERICYTOMA + HEMOLYTIC ANEMIA
In the case presented here, a metastasizing hemangiopericytoma of the pancreas and retroperitoneum had extensively invaded the liver and other organs and had somehow become associated with a microangiopathic hemolytic anemia. One must think beyond the facts. We do not know the origin of the anemia. We cannot be certain of which came first, the anemia or the metastasis. The initiating factors of this type of extracorpuscular hemolytic anemia in a setting of vascular injury are still a matter of conjecture. What is the actual pathomechanism of this fatal combination of pathologic lesions? It is possible that tumor cell aggregates initiated the disruption of the integrity and continuity of vascular endothelium. It is also possible that the vicious cycle of fibrin precipitation, platelet aggregation, erythrocyte fragmentation, chemical releases from ruptured cells and an extracorpuscular hemolytic anemia and thrombocytopenia resulted therefrom. But we have no adequate proof. If there is a common denominator for metastasis and anemia in these cases, it is probably related to the defense mechanism of the host. This patient may have been manufacturing cancer cells for many years. It could be that for some reason she lost the humoral substances and antibodies that were keeping her safe by destroying the malignant cells as they formed. Perhaps blocking antibodies were present, but this would not be the only way. A fibrinolysis or microangiopathic hemolysis could be at fault. The breakdown of a total host response might embody many things. Genetically changed cells, tumor specificity of antigens and humoral substances, loss of antigens, genetic changes on the surface of cells, variable effects of viral infection, misdirected immunologic responses, abnormal B cells or T cells and immune globulin disturbances-any or all of these are possible factors in a breakdown of host resistance.. Ever since Ewing established the histogenetic classification of tumor cells in 1919, the pathologist has been the arbiter of most of the issues in cancer. In the present case, as in most cases of malignancy today, the pathologist's contribution is becoming only a portion of the pie. A hemangiopericytoma which was relatively dormant for many years and so small that it was clinically undetectable only a few months before its rapid spread, must have undergone some major alteration unknown to us. Was this due to genetic changes (22), antigenic changes or alterations in host response? Viruses can cause leukemia
(23-25). But if a virus was the etiologic factor in our patient, why wasn't the malignancy in the form of leukemia? In this case, a breakdown in host response appears to be the most logical hypothesis. Whether or not there is a common pathway for this and other metastatic malignant lesions, the present state of our knowledge limits us in making an appraisal. We can only depend on the contributions of research to date. But rather than the strictly pathologic view, we should be thinking also in terms of immunologic surveillance, cytogenetics, biochemistry (e.g., defective aerobic glycolysis), endocrine disturbances and other approaches. The initiating factor of the extracorpuscular hemolytic anemia in this woman may have been aggregates of tumor cells, but it is also possible that the anemia and not the tumor cells set things in motion by some elusive mechanism which researchers may soon discover. In the near future it may even be possible to use detection of microangiopathic hemolytic anemia in a patient with a previously diagnosed tumor as an indication that metastatic disease has developed (20, 26-30). REFERENCES 1. Stout AP and Murray MR: Hemangiopericytoma; a vascular tumor featuring Zimmermann's pericytes, Ann Surg 116: 26, 1942. 2. O'Brien P and Brasfield RD: Hemangiopericytoma, Cancer 18: 249, 1965. 3. Fernando NVP and Movat HZ: The fine structure of the terminal vascular bed. III. The capillaries, Exper Molec Path 3: 87, 1964. 4. Movat HZ and Fernando NVP: The fine structure of the terminal vascular bed. IV. The venules and their perivascular cells, Exper Molec Path 3: 98, 1964. 5. Stout AP: Tumors featuring pericytes; glomus tumor and hemangiopericytoma, Lab Invest 5: 217, 1956. 6. Hakala TR, Page D and Fleischli DJ: Paravesical hemangiopericytoma, J Urol 103: 436, 1970. 7. Greene RR, Gerbie AB and Eckman TR: Hernangiopericytomas of the uterus, Am JObst Gynec 106: 1020, 1970. 8. Backwinkel KD and Diddams JA: Hemangiopericytoma; report of a case and comprehensive review of the literature, Cancer 25: 896, 1970. 9. Ayella RJ: Hemangiopericytoma; a case report with arteriographic findings, Radiology 97: 611, 1970. 10. Hahn MJ, Dawson R, Esterly JA et al: Hemangiopericytoma; an ultrastructural study, Cancer 31: 255, 1973. 11. Sugar HS, Fishman GR, Kobernick S et al: Orbital hemangiopericytoma or vascular meningioma, Am J. Ophthalmol 70: 103, 1970. 12. Gurney N, Chalkley T and O'Grady R: Lacrimal sac hemangiopericytoma, Am J Ophthalmol 71: 757, 1971. 13. Reymond RD, Hazra TA and Edlow DW: Hernangiopericytoma of the vulva with metastasis to bone 14 years later, Brit J Radiol 45: 765, 1972.
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KUPERS ET AL. 14. Silverberg SG, Willson MA and Board JA: Hemangiopericytoma of the uterus: an ultrastructural study, Am J Obst & Gynec 110: 397, 1971. 15. Lambert MB and Daw E: Hemangiopericytoma of the uterus, Practitioner 210: 255, 1973. 16. Kirshen EJ, Naftolin F and Benirschke K: Uterine hemangiopericytoma in a 19-year-old woman, Obst Gynec 40: 652, 1972. 17. Shugart RR: Glomus tumors and hemangiopericytomas of the extremities and trunk. Thesis, Graduate School, University of Minnesota, 1961. 18. Harrison HC and Bulteau V: Hemangiopericytoma of the nasal cavity, Aust NZ J Surg 41: 251, 1972. 19. Alii AF and Singh SP: Hemangiopericytoma in the nasal cavity in Ibadan, Nigeria, J Laryngol 86: 405, 1972. 20. Lohrman HP, Wolfgang A and Heymer B: Microangiopathic hemolytic anemia in metastatic carcinoma; report of eight cases, Ann Int Med 79: 368, 1973. 21. Brain MC, Dacie JV and Hourihane DO: Microangiopathic hemolytic anemia: the possible role of vascular lesions in pathogenesis, Brit J. Haemat 8: 358, 1962. 22. Sandberg AA and Hossfeld DK: Chromosomal abnormalities in human neoplasia, Ann Rev. Med 21: 379, 1970.
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23. M.D. Anderson Hospital & Tumor Institute: Carcinogenesis: A Broad Critique. Baltimore, Williams & Wilkins, 1967. 24. Holland JF and Frei E: Cancer Medicine. Philadelphia, Lea & Febiger, 1973. 25. M.D. Anderson Hospital & Tumor Institute: The Proliferation and Spread of Neoplastic Cells. Baltimore, Williams & Wilkins, 1968. 26. Brain MC: Microangiopathic hemolytic anemia, Ann Rev Med 21: 133, 1970. 27. Joseph RR, Day HJ, Sherwin RM et al: Microangiopathic hemolytic anemia associated with consumption coagulopathy in a patient with disseminated carcinoma, Scandinar J Hematol 4: 271, 1967. 28. Levin H: Microangiopathic hemolytic anemia: the pathogenesis of red blood cell fragmentation; a review of the literature, Aerospace Med 41: 331, 1970. 29. Tapp E and Ralston A: Thrombotic microangiopathy associated with squamous carcinoma, Brit Med J 4: 209, 1969. 30. Bull BS and Kuhn IN: The production of schistocytes by fibrin strands (a scanning electron microscope study), Blood 35: 104, 1970.
