Anemia of Chronic Disease

The most common anemia in patients withcancer is anemia of the chronic diseasetype. In a useful oversimplification, patients with cancer can be said to be anemicbecause they are sick, since the anemiaseen in advanced cancer is similar to theanemia of chronic infectious and chronicinflammatory disorders.2 The precisemechanism for the anemia of chronic disease has not been defined. Unappreciateddifferences that may exist between the anemia of cancer and the anemia of otherchronic diseases —¿�unique tumor-relatedmediators, for example—have been described.34

Although a shortened survival of redblood cells has been noted in the anemia ofchronic disease, the primary defect is arelative decrease in the production of redblood cells. Red blood cells are typicallynormochromic and normocytic, althoughmicrocytosis and hypochromia may bepresent. The level of serum iron is low, andan erroneous diagnosis of iron deficiencymay be made; however, in contrast to irondeficiency, the serum iron-binding capacityislow.The levelofserumferritinmay notaccuratelyreflectironstores,becausethelevelcan be elevatedin thepresenceofcancer.Bone marrow aspirationmay benecessarytodistinguishtheanemiaofad

Introduction

Anemia, the most common hematologicabnormality in patients with cancer,' isoften the clue that, when appropriately pursued, leads to the original diagnosis of cancer. It is also a manifestation of cancer; themajority of patients with advanced cancerare anemic.

The evaluation of anemia in a patientwith cancer is an intellectual challenge tothe physician because of the interesting andvaried number of reasons why patients withcancer become anemic. The physician's efforts to explain anemia will be rewarded bya better understanding of what is happeningto the patient and by the physician's abilitytoinitiaterationaltreatment.

The properinitialapproachtotheevaluation of a patient with anemia is to understand the patient's clinical situation andknow what to expect under those conditions. Some of the ways patients with cancer become anemic are reviewed in thetable.

Dr. Steinberg is Head of the Section of Hematology at Lahey Clinic Medical Center in Burlington. Massachusetts, and Clinical AssistantProfessor of Medicine at Harvard MedicalSchool in Boston, Massachusetts.

CA-ACANCERJOURNALFORCLINICIANS296

Anemia and Cancer

DavidSteinberg,MD

vanced cancer from iron deficiency. In anemia of chronic disease, normal or increasediron in bone marrow reticuloendothelialcells is present, and in iron deficiency, bonemarrow iron stores are depleted.

In anemia of chronic disease, the flowof iron from the reticuloendothelial systemto the red blood cells is impaired.2 Anemiausually is mild to moderate in severity.When the hemoglobin concentration is lessthan nine g/dL, other causes should be considered. Treatment is directed at the underlying illness. Anemia is usually not sufficiently severe to warrant transfusions of redblood cells.

Anemia of chronic disease can be thediagnostic clue that leads to the originaldiagnosis of cancer. A careful search foroccult chronic disease in a patient presenting with anemia of chronic disease mayreveal a tumor (kidney and pituitary glandtumors, for example, and sometimes evenmetastatic cancer), especially when thesymptoms related to the tumor are otherwise subtle.

Pure Red Blood Cell Aplasia

Pure red blood cell aplasia, the selectiveabsence of red blood cell precursors in thebone marrow, is an uncommon problemthat is associated with various tumors; italso can antedate the diagnosis of cancer.Anemia can be severe, and transfusions ofred blood cells may be needed.

About one half of patients with redblood cell aplasia have a thymoma, and onethird of these patients recover from anemiawhen the thymoma is removed.5 A varietyof other tumors have been associated withred blood cell aplasia, including Hodgkin'sdisease; non-Hodgkin's lymphomas; lung,breast, thyroid, and biliary tract cancers;and cancer of unknown primary origin.3Red blood cell aplasia also has been associated with acute leukemia,6 chronic lymphatic leukemia,7 chronic myeloid leukemia,8 and myeloid metaplasia.8

Red blood cell aplasia may be an autoimmune disease. A variety of other autoimmune phenomena are seen in patientswith red blood cell aplasia.5 Abnormal sup

pressor T cells that inhibit erythropoiesishave been found.7 In other patients, agamma globulin that inhibits erythropoiesishas been detected.―2 Response to treatmentwith immunosuppressive agents supportsan immune cause. Patients have beentreated successfully with cyclophosphamide, steroids, a combination of cyclophosphamide and steroids, and antithymocyte globulin.57

Treatment-Related Anemia

Itcanbedifficulttodistinguishtheanemiathat results from treatment from anemiacaused by other factors. Nonetheless,chemotherapeutic agents, such as the alkylating agents including the nitrosoureas,dactinomycin, and cisplatin, can suppressthe production of red blood cells.9 Anemiahas been reported in nine to 40 percent ofpatients receiving cisplatin. In some ofthese patients, anemia has been severe.9―0

Drugs that inhibit DNA synthesis canproduce megaloblastic anemia. This complication has been seen with hydroxyurea,cytarabine. methotrexate, 5-fluorouracil,thioguanine, azathioprine, and 6-mercaptopurine.@

Hemolytic anemia has been describedwith cisplatin. The drug is adsorbed ontothe red blood cell, where antibodies to cisplatin mediate destruction of red bloodcells.'4'5Some cytotoxicdrugscauseincreased oxidant stress. Carmustine can reduce glutathione reductase and cause increased hemolysis in patients with glucose6-phosphate dehydrogenase (G6PD) deficiency.9 Doxorubicin can generate reactiveoxygen compounds, and oxidative hemolysis has been described in a patient withG6PD deficiency.9 Pentostatin is anotherantineoplastic drug reported to cause hemolytic anemia.'5

Acute leukemia has developed in somepatients with Hodgkin's disease, nonHodgkin's lymphomas, multiple myeloma,or ovarian cancer, who have been treatedsuccessfully with drug programs that include alkylating agents. Often a preleukemic phase characterized by anemia andother cytopenias exists. Anemia, as part

VOL.39,NO.5 SEPTEMBER/OCTOBER1989 297

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of a chemotherapy-inducedpreleukemicstate,canbeassociatedwithahyperplastic,dysplastic.or sideroblasticbone marrow. 16.17

Radiationtherapyismyelosuppressiveand can also contribute to anemia in patients with cancer.

A dose-dependent anemia develops inpatientswithacquiredimmune deficiency

The evaluationof anemia in a patient

with canceris an intellectual challenge

because ofthe interesting and varied

number of reasonswhy patients with cancer

become anemic.

syndrome (AIDS), many with cancer,when they are treated with the inhibitor ofviralreplication,zidovudine (Retrovir[AZT]).The anemiaoftenissevere,requiring transfusions of red blood cells. A selective bone marrow erythroid hypoplasia hasbeen observed.'8

Myelophthisic Anemia

Anemia can be caused by bone marrowinvolvement with both hematologic andnonhematologic cancers. An importantclue to the presence of bone marrow involvement is a leukoerythroblastic bloodpicture. This refers to the presence in theperipheral blood of immature granulocytesand nucleated red blood cells. When bonemarrow involvement and cancer coexist,red blood cell morphology may be abnormal, with teardrop-shaped red blood cells.Some patients with bone marrow involvement also have neutropenia and thrombocytopenia. Tumors that commonly involvethe bone marrow include prostate, breast,and stomach cancers; small cell lung carcinoma; lymphoma; and malignant mela

noma. The diagnosis of bone marrow involvement is made by bone marrow biopsy.

Bleeding and Iron Deficiency

Bleeding. either overt or occult. may be theclue that leads to the initial diagnosis ofcancer. When blood loss persists. iron deficiency may develop. It should be axiomatic that until proved otherwise, iron deficiency means bleeding. and the source ofbleeding should be identified. In patientswith tumors that have required gastric resection. iron deficiency may develop because of decreased iron absorption.

In the patient with typical iron deficiency, the diagnosis is made by demonstration of a low level of serum iron and anelevated level of total iron-binding capacity; however, when chronic illness, such asmetastatic cancer, also exists, the diagnosisof iron deficiency may be difficult to establish. When the levels of serum iron and thetotal iron-binding capacity are low, it isdifficult to know whether this is a result ofchronic disease alone or chronic diseaseand iron deficiency. Knowledge of the levelof serum ferritin can be helpful if it is low,but it is often elevated because of cancer,especially when liver disease is present. Ifit is important to establish the diagnosiswith certainty, bone marrow aspiration isoften the best way to determine whetheriron deficiency exists.

There are many reasons for bleeding ina patient with cancer. When anemia develops, bleeding and iron deficiency alwaysshould be considered possible causes.

Megaloblastic Anemia

Patients with cancer may have megaloblastic anemia as a result of folic acid deficiency, which is caused by anorexia anddecreased dietary intake.3 In patients withsmall bowel disease or in patients who havehad small bowel resection, megaloblasticanemia can be caused by malabsorption ofeither folic acid or vitamin B,2.

Increased requirements for folic acidthat cannot be met by dietary intake canresult from increased cellular proliferation

CA-A CANCERJOURNALFORCLINICIANS300

cancer (10 percent of patients).23 Pathologic abnormalities in the small blood vessels consist of tumor emboli in 60 percentof patients,23fibrinmicrothrombiin 50

Anemiais often the clue

that, when appropriatelypursued,

leads to the originaldiagnosisof cancer.

percent of patients,23 and less commonlyvascular hypertrophy with intimalhyperplasia.24 Tumor emboli and fibrin microthrombi often coexist. Tumor cells mayinduce local intravascular coagulation withthe formation of fibrin microclots.

Fragmentation of red blood cells iscaused by mechanical shearing as red bloodcells traverse abnormal small blood vessels.3 Hemolytic anemia can have an abruptonset and typically is severe. Haptoglobinlevels are low, and hemoglobinuria may bepresent.3'23 Thrombocytopenia is presentfrequently. Anemia is treated with transfusions of red blood cells and, when possible,by treating the tumor. Survival in thesepatients is short because they have widespread cancer.

Microangiopathic hemolytic anemiahas alsobeen seenwithvasculartumors,such as hemangioendothelioma and hemangiosarcoma.Red blood cellssuffermechanical damage as they traverse theanastomosing vascular channels that characterize these tumors.25-'28

Antineoplastic drugs can induce a syndrome that is similar to the hemolyticuremic syndrome and rarelysimilartothrombotic thrombocytopenic purpura.2329MitomycinC isby farthemostcommonlyimplicated drug. Bleomycin and cisplatinhave also been reported to cause this syndrome.23 The syndrome is dose-related,and the median onset is 11.5 months afteradministration of mitomycin is started.Many patients with this syndrome eitherwere in clinical remission or were being

and have been described as a cause of megaloblastic anemia in leukemia, lymphoma.and multiple myeloma. 19.22In patients withmyeloproliferative disorders, especiallymyelofibrosis,megaloblasticanemia mayalso develop because of increased requirements for folic acid caused by an increasedturnover of hematopoietic cells.'9 It is important to make this diagnosis, becausemany of these patients respond to treatmentwith folic acid. Unfortunately, however,treatment with folic acid, particularly inleukemia, may cause increased proliferation of the cancer.3

Patients who have been treated by gastrectomy or subtotal gastrectomy are at increased risk for the development of megaloblastic anemia because of vitamin B,2malabsorption. Megaloblastic anemia, aspreviously noted, can also be caused bychemotherapy (see the section on treatment-related anemia).

Microangiopathic Hemolytic Anemia

A look at the peripheral blood smear is wellrewarded when fragmented red blood cells(schistocytes)areseen.In theabsenceofvalvular heart disease, schistocytes indicate microangiopathy (small blood vesseldisease). Non-neoplastic small blood vessel disorders that can produce a microangiopathicbloodsmear includevasculitis,thrombotic thrombocytopenic purpura,malignant hypertension, amyloid, and fibrim clot as seen in disseminated intravascular coagulation. Microangiopathy withhemolytic anemia can also be seen in patients with cancer. Its cause may be thetumor or certain chemotherapeutic agents.

Microangiopathic hemolytic anemiaassociated with carcinoma is typically seenwith widespread metastatic disease, usually andenocarcinoma.3'23 However, it hasalso been described, although less frequently, with squamous cell carcinoma,undifferentiated carcinoma, small cell carcinoma, and thymoma.23 The most common tumors associated with microangiopathic hemolytic anemia are gastriccarcinoma(52percentofpatients),breastcancer(13 percentof patients),and lung

VOL.39, NO. 5 SEPTEMBER/OCTOBER1989 301

givenadju@anttreatmentand had minimalor no cancer. The major clinical findings,inadditiontomicroangiopathichemolyticanemia,are thrombocytopeniaand renalinsufficiency that often requires dialysis.

The proper initialapproach

is to understand the patient'sclinical situation

and know what to expectunder these

circumstances.

Other findings include neurologic abnormalities, pericarditis, hypertension, noncardiogenic pulmonary edema, and congestive heart failure.

It is believed that these antineoplasticagents damage the endothelium. and thisdamage leads to microvascular abnormalities, especially in the kidney. Pathologicchanges are identical to those described inthe hemolytic-uremic syndrome. 23.29

Chemotherapy-related microangiopathy is associated with a high mortality. Theoffending drug should be stopped. and. ifpossible. blood transfusion shouldbe avoided (transfusion exacerbates thesyndrome).

the most common condition seen with autoimmune hemolytic anemia. Autoimmunehemolytic anemia develops in up to 25 percent of patients with chronic lymphatic leukemia.3 30Autoimmune hemolytic anemiais also seen with other forms of acute andchronic leukemia, although much less frequently.33°The development of autoimmune hemolytic anemia in association withcancer is often an unfavorable prognosticsign.330 Autoimmune hemolyticanemiadevelopsinabouttwo tothreepercentofpatientswith non-Hodgkin'slymphomasand Hodgkin'sdisease.3@30Autoimmunehemolyticanemiahasalsobeenassociatedwithangioimmunoblasticlymphadenopathy, a condition that can be confused withlymphoma, and can also evolve into lymphoma. It has also been described inassociationwith multiplemyeloma andthymoma. @°

The incidenceof autoimmune hemolyric anemia in solid tumors is low, and therelationshipinmany instancesmay simplybe coincidental.Varioussolidtumors,as

Theincreased survival

of patientswith cancer makes it important

to consider the possibilitythat the anemia

is unrelated to the originalcancer.

Autoimmune Hemolytic Anemia

In warm autoimmune hemolytic anemia,an antibody. which is usually an IgG molecule, attaches to red blood cells and mediates their destruction, predominantly inthe spleen. Results of the direct IgG antiglobulin test (Coombs' test) are typicallypositive. Spherocytes may be seen in theperipheral blood smear. and when the bonemarrow can respond normally. reticulocytosis is present. The haptoglobin levelmay be low.

Warm autoimmune hemoly'tic anemiamay be associated with reticuloendothelialneoplasia. Chronic lymphatic leukemia is

wellasbenignovariantumors,havebeenassociatedwith autoimmune hemolyticanemia.3°

Autoimmune hemolyticanemiacanoccur simultaneouslywiththediagnosisofcancer.Autoimmune hemolyticanemiacandevelopinthecourseofthemalignantdisorderor.lesscommonly, can antedatethecancer.3

Treatment of the associated tumor, particularly if it can be resected surgically,may result in resolution of autoimmunehemolysis. 331 Often, however, especially

302 CA-A CANCERJOURNALFORCLINICIANS

with leukemia and lymphoma, the underlying cancer and the autoimmune hemolytic anemia follow therapeutically independent courses.3'

In cryopathic hemolytic anemia, anautoantibody, usually of the 1gM type,fixesto red blood cellsat temperaturesbelow37°C. Destructionofredbloodcellsis mediated by complement fixation andmay be intravascular or occur in the liver.3Hemoglobinemia, hemoglobinuria, hemosiderinuria, a low level of haptoglobin, andreticulocytosis may be present. The diagnosis is established by demonstrating thepresence of cold agglutinins. In addition tohemolysis, some patients also have vasoocclusive symptoms—most commonly,Raynaud's phenomenon.

Hemolysis resulting from cold agglutinins. is less common than warm autoimmune hemolytic anemia and is seenin association with lymphoproliferativedisorders, in particular Waldenström'smacroglobulinemia, non-Hodgkin's lymphomas, and chronic lymphatic leukemia.32 Chronic hemolysis resulting fromcold agglutinins, in the absence of histologic evidence of cancer, is called chroniccold agglutinin disease. The nature of thisdisorder is unclear, but it resembles alymphoproliferative disorder. 32

References

Hypersplenism

Anemia caused by hypersplenism may beassociated with either neutropenia orthrombocytopenia or both. Anemia iscaused by the pooling of red blood cells inan enlarged spleen, decreased survival ofred blood cells, and hemodilution resultingfrom an increased plasma volume.3'33 Inuncomplicated cases, the bone marrowshows erythroid hyperplasia. The diagnosisof hypersplenism is confirmed with certainty only retrospectively when anemiaand other cytopenias resolve after splenectomy.

Hypersplenism caused by cancer ismost commonly seen in lymphoproliferativeandmyeloproliferativedisorders.@

Unrelated Causes

Many patients with cancer are either curedor survive for years. For some patients,problems unrelated to the cancer will develop. Pernicious anemia may coincidentally develop in a patient cured of large celllymphoma. A patient cured of Hodgkin'sdisease may have a bleeding ulcer. Theincreased survival of patients with cancermakes itimportanttoconsiderthepossibility that anemia is unrelated to the originalcancer. [€1

1. Banerjee RN, Narang RM: Hematologicchanges in malignancy.Br J Haematol13:829—843,1967.2. Zucker 5: Anemia in cancer. Cancer Invest3:249—260,1985.3. Doll DC, WeissRB: Neoplasiaandtheerythron. J Clin Oncol 3:429—446, 1985.4. LoughlinKR, GittesRF,PartridgeD.StelosP: The relationship of lactofemn to the anemiaofrenalcellcarcinoma.Cancer59:566—571.1987.5. Krantz SB: Pure red-cell aplasia: Seminarsin medicine of the Beth Israel Hospital, Boston.N Engi J Med 291:345—350.1974.

6. Dessypris EN, Fogo A, Russell M, et al:Studies on pure red cell aplasia. X. Associationwith acute leukemia and significance of bonemarrow karyotype abnormalities. Blood56:421—426,1980.7.RadosevichCA, GordonLI,WeilSC,etal:Completeresolutionofpureredcellaplasiainapatientwithchroniclymphocyticleukemiafollowing antithymocyte globulin therapy. JAMA259:723—725.1988.8. Dessypris EN, McKee CL Jr. MetzantonakisC. etal:Red cellaplasiaandchronicgranulocyticleukaemia.Br J Haematol48:217—225,1981.

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9. Doll DC, Weiss RB: Chemotherapeuticagents and the erythron. Cancer Treat Rev10:185—200,1983.10. Kuzur ME, Greco FA: Cisplatin-inducedanemia (letter). N Engl J Med 303:110—111,1980.11.ScottJM, WeirDG: Drug-inducedmegaloblasticchange.ClinHaematol9:587—606,1980.12. Talley RW, Vaitkevicius VK: Megaloblastosis produced by a cytosine antagonist, 1-betaD-arabinofuranosylcytosine. Blood 2 1:352—362, 1963.13. Borne P. ClarkPA: Megaloblasticanaemiaduring methotrexatetreatment of psoriasis. BrMedJ 1:1339,1966.14.GetazEP,Beckley5,FitzpatrickJ,DozierA: Cisplatin-induced hemolysis. N Engl J Med302:334—335,1980.15.DollDC, WeissRB:Hemolyticanemiaassociated with antineoplastic agents. CancerTreat Rep69:777—782,1985.16. Kitahara M, Cosgriff TM, Eyre HJ:Sideroblastic anemia as a preleukemic event inpatients treated for Hodgkin's disease. Ann Intern Med 92:625—627,1980.17. Casciato DA, Scott JL: Acute leukemia following prolonged cytotoxic agent therapy. Medicine 58:32—47,1979.18. Walker RE, Parker RI, Kovacs JA, et al:Anemia and erythropoiesis in patients with theacquired immunodeficiency syndrome and Kaposi's sarcoma treated with zidovudine. AnnInternMed 108:372—376,1988.19. Hoffbrand AV, ChanarmnI, Kremenchuzky5, et al: Megaloblastic anaemia in myelosclerosis. QJMed37:493—5l6, 1968.20. ChanarmnI: Folate deficiency in the myeloproliferativedisorders.Am J Clin Nutr23:855—860,1970.21. RoseDP: Folic acid deficiencyin leukemiaand lymphomas. J Clin Pathol 19:29—32,1966.

22.HoffbrandAV, HobbsJR,KremenchuzkyS. MolinDL: Incidenceand pathogenesisofmegaloblasticerythropoiesisinmultiplemyeloma. J Clin Pathol 20:699—705,1967.23. Murgo AJ: Thrombotic microangiopathy inthecancerpatientincludingthoseinducedbychemotherapeuticagents.Semin Hematol24:161—177,1987.24.AntmanKH, SkarinAT, MayerRJ,etal:Microangiopathichemolyticanemiaandcancer:A review.Medicine58:377—384,1979.25.AlpertLI.BcnischB: Hemangioendotheliomaoftheliverassociatedwithmicroangiopathic hemolytic anemia: Report of four cases.AmJ Med48:624—628,1970.26. Arnn ET. Yam LT, Li C: Systemic angioendotheliomatosispresentingwithhemolyticanemia. Am J Clin Pathol 80:246—251,1983.27. Donald D, Dawson AA: Microangiopathichaemolyticanemiaassociatedwithmalignanthaemangio-endothelioma.J Clin Pathol24:456—459,1971.28. Scully RE. Galdabini JJ, McNeely BU:Case records of the Massachusetts GeneralHospital (Case 4—1980). N EngI J Med302:283—289,1980.29. Cantrell JE Jr. Phillips TM. Schein PS:Carcinoma-associated hemolytic-uremic syndrome: A complication of mitomycin C chemotherapy. J Clin Oncol 3:723—734,1985.30.PirofskyB: Autoimmunizationand theAutoimmuneHemolyticAnemias.Baltimore,Williams& Wilkins,1969.31.PirofskyB: Immune haemolyticdisease:The autoimmunehaemolyticanaemias.ClinHaematol4:167—180,1975.32.CrispD, PruzanskiW: B-cellneoplasmswith homogeneouscold-reactingantibodies(coldagglutinins).Am J Med 72:915—922,1982.33.BowdlerAJ: Splenomegalyand hypersplenism.ClinHaematol12:467—488,1983.

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