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CHAPTER 40 ANEMIA ASSOCIATED WITH MARROW INFILTRATION

CHAPTER 40 ANEMIA ASSOCIATED WITH MARROW INFILTRATION
Williams Hematology

CHAPTER 40 ANEMIA ASSOCIATED WITH MARROW INFILTRATION

ALLAN J. ERSLEV

Definition and History
Etiology and Pathogenesis
Clinical Features
Laboratory Features
Differential Diagnosis
Therapy, Course, and Prognosis
Chapter References

Myelophthisic anemia is a term used to describe the hematologic consequences of bone marrow infiltration. It can range from an overt leukoerythroblastic picture to the presence of a few teardrop-shaped red cells on a blood film. These changes may indicate the presence of early spread of a tumor and may herald eventual replacement of active marrow space. The traditional diagnostic bone marrow sampling has now been augmented by magnetic resonance images of bone.

Acronyms and abbreviations that appear in this chapter include: MRI, magnetic resonance imaging.

DEFINITION AND HISTORY
The presence of minimal and spotty marrow infiltrations with abnormal cells or tissue components does not usually cause symptoms or hematologic changes. Such infiltrations are, however, of considerable clinical significance. In patients with an established diagnosis of cancer they indicate metastatic dissemination of the tumor. In patients treated with chemotherapy they suggest inadequate treatment. Extensive infiltration may also be well tolerated, but when associated with disruption of the normal marrow structure it may cause the development of an anemia or pancytopenia designated as a myelophthisic anemia.1 Such an anemia is characterized by the presence on the blood film of schistocytes and teardrop-shaped red cells and often by prematurely released nucleated red cells, megakaryocytic fragments, and immature myeloid cells. When pronounced, this condition is referred to as leukoerythroblastosis.2
ETIOLOGY AND PATHOGENESIS
The most common causes of extensive cellular infiltration of marrow are listed in Table 40-1. In chronic leukemias the invading cells will usually not cause structural damage but live in a peaceful symbiosis with normal marrow constituents. Eventually, however, the expansion of the volume of pathologic cells and the release of suppressor cytokines will lead to anemias and other cytopenias, but without the characteristic morphologic features of myelophthisis. In myelofibrotic disorders, both agnogenic and secondary, megakaryocytes will release fibroblastic growth factors, with the subsequent reduction in available bone marrow space and disruption of its architecture (see Chap. 78). This will cause cytopenias with the production of deformed red cells, especially poikilocytes and teardrop-shaped cells, and the premature release of erythroblasts, myelocytes, and giant platelets (see Chap. 29). A similar picture can be seen when the marrow is replaced by macrophages containing indigestible lipids, as in Gaucher disease.

TABLE 40-1 MARROW INFILTRATION

The invasion of metastatic cancer cells will cause the early release of suppressive and destructive cytokines, leading to the development of a myelophthisic blood picture even before the marrow is completely replaced.3,4 The marrow microenvironment is second only to the lung and comparable to the liver in its susceptibility to implantation of blood-borne malignant cells. Almost all cancers can metastasize to the marrow,5,6 but the most common are cancers of the lung, breast, and prostate. Metastatic foci in the marrow can be found in 20 to 30 percent of patients with small cell carcinoma of the lung at the time of diagnosis and in more than 50 percent at autopsy.7 The prevalence, especially at diagnosis, is lower in patients with cancer of the breast and prostate but is still sufficiently high to make marrow biopsy an important diagnostic and prognostic procedure.8,9 and 10 The development of frank leukoerythroblastosis occurs much less frequently,11 and its absence should not be relied upon to indicate that marrow involvement has not occurred.
The characteristic abnormalities in hematopoiesis observed in patients with chronic myelophthisic anemia may in part be due to compensatory extramedullary blood formation. Splenic and hepatic microvasculature, especially when affected by the underlying disease, are not as effective in producing normal blood cells as is the marrow. Splenic infiltration may also result in hypersplenic sequestration and destruction of blood cells. In addition, the underlying disease, especially in metastatic malignancies, may contribute infectious and nutritional complications affecting the blood picture of patients with infiltrative disease of the marrow.
CLINICAL FEATURES
Symptoms and signs associated with infiltrative marrow disorders are usually related to the underlying disease. However, pain and tenderness of affected bones, pathologic fractures, and hypercalcemia causing nausea, symptoms of anemia, muscle weakness, or stupor may bring patients to medical attention.
LABORATORY FEATURES
The anemia is mild to moderate. The white cell and platelet counts may vary, but the most characteristic feature is the morphologic appearance of red cells on the blood film. These cells may show anisocytosis and poikilocytosis, but the presence of teardrop forms and nucleated red cells is particularly suggestive of marrow infiltration (Fig. 40-1). The combination of nucleated red cells and immature myeloid precursors constitutes the leukoerythroblastotic picture that when present is so characteristic of marrow infiltration. The leukocyte alkaline phosphatase score is normal or increased, and the karyotype of remaining normal marrow cells is intact. The presence of cancer cells on the blood film (carcinocythemia) occurs occasionally and always indicates marrow invasion.12 Marrow biopsy is the most reliable procedure by which to make a diagnosis of marrow-infiltrative disease and should be carried out in all patients with suspected metastatic carcinoma or hematologic features of myelophthisic anemia.13 Marrow aspirations are also of value14 but may not provide the same yield of tumor cells and can be difficult to interpret in patients with agnogenic or secondary myelofibrosis.15 Marrow biopsy or aspiration is best performed in areas with tender bone, and inability to aspirate marrow from such a tender bone (dry tap) leads to a high degree of suspicion of marrow replacement. Since the diagnostic marrow yield from biopsies depends on the amount of tissue examined, a single negative biopsy should be repeated. An isotopic bone scan showing a focal accumulation of radioactive tracers can be helpful in locating a suitable site for biopsy,16 but a negative study of the area does not exclude the possibility of marrow involvement. MRI using T1-weighted images is being used with increasing frequency since it is capable of demonstrating sites of altered marrow activity, thus indicating suitable areas for biopsy.17,18 and 19

FIGURE 40-1 Blood film of a patient with prostatic adenocarcinoma metastatic to the marrow. The film shows an early myeloid cell, a nucleated red cell, and a classic teardrop-shaped red cell.

DIFFERENTIAL DIAGNOSIS
A myelophthisic blood picture ranging from a few teardrop-shaped red cells on the blood film to a full-blown leukoerythroblastic picture demands close attention. An underlying disease causing marrow infiltration may already have been diagnosed, but in the case of malignancies the blood picture may suggest metastatic spread and demand verification by repeated bone marrow biopsies and the use of MRI. In patients treated for a neoplastic disorder careful bone marrow examination, even in the absence of red cell changes, may also be in order to exclude foci of surviving neoplastic cells. Such an attempt may today be augmented by a sophisticated immunologic flow cytometry study using appropriate antibodies.20 Leukoerythroblastosis may occur in conditions other than cancer metastatic to the marrow.21 Of these, the most important are consumptive microcoagulopathy, severe blood loss, and transient hypoxia. Myelophthisic anemia with or without leukoerythroblastosis has also been described in patients with hepatitis,22 ulcerative colitis,23 and anorexia nervosa.24 Idiopathic myelofibrosis, a common cause of myelophthisic anemia among the aged, may be difficult to distinguish from metastatic disease with focal reactive fibrosis15 and should be considered in the differential diagnosis (see Chap. 29).
THERAPY, COURSE, AND PROGNOSIS
The goal of treatment is, in general, to manage the underlying disease. If the anemia is caused in part by extramedullary disease processes such as splenomegaly in idiopathic myelofibrosis, gratifying although temporary improvement can be expected after splenectomy. Patients with marrow infiltration caused by leukemia, cancer, or lymphoma should be treated appropriately, since the presence of marrow infiltration may not adversely affect the outcome. If treatment is successful there may be complete disappearance not only of the malignant cells but also of the reactive fibrosis surrounding metastatic foci. Treatment of metastatic lesions with the bone-seeking isotope strontium-89 has been tried, but usually causes unacceptable hematopoietic suppression.25 Supplementation with recombinant erythropoietin has been found useful in infiltrative marrow disorders.26 In hormone-refractory prostate cancer the presence of leukoerythroblastic reaction does not seem to influence survival,27 but unfortunately in most patients with cancers metastatic to the marrow, the prognosis is for only short-term survival.
CHAPTER REFERENCES

1.
Rundles RW, Jousson U: Metastases in the bone marrow and myelophthisic anemia from carcinoma of the prostate. Am J Med Sci 218:240, 1949.

2.
Vaughan JM: Leuco-erythroblastic anaemia. J Pathol Bacteriol 42:541, 1936.

3.
Abasov IT: The state of the peripheral blood in cancer metastases to bone marrow. Haematologica (Pavia) 2:381, 1968.

4.
Laszlo J: Hematologic effects of cancer, in Cancer Medicine, 2d ed, edited by JF Holland, E Frei, p 1275. Lea and Febiger, Philadelphia, 1982.

5.
Schwartz RA, De-Jager RL, Janniger CK, Lambert WC: Giant basal cell carcinoma with metastases and myelophthisic anemia. J Surg Oncol 33:223, 1986.

6.
Newman HF, Howard GC, Reid PM: Metastatic oligodendroglioma presenting as a leukoerythroblastic anaemia. Eur J Surg Oncol 11:287, 1985.

7.
Hirsch FR, Hansen HH: Bone marrow involvement in small cell anaplastic carcinoma of the lung: Prognostic and therapeutic aspects. Cancer 46:206, 1980.

8.
Cohen Y, Gershoni-Baruch R, Lichtic C: Bone marrow biopsy in patients with malignant neoplasms other than lymphomas or leukemia. Acta Haematol (Basel) 62:181, 1979.

9.
Savage RA, Hoffman GC, Shaker K: Diagnostic problems involved in detection of metastatic neoplasms by bone marrow aspirate compared with needle biopsy. Am J Clin Pathol 70:623, 1978.

10.
Chemow B, Wallner SF: Variables predictive of bone marrow metastasis. Cancer 42:2373, 1978.

11.
Delsol G, Guiu-Godfrin B, Guiu M, et al: Leukoerythroblastosis and cancer frequency, prognosis, and physiopathologic significance. Cancer 44:1009, 1979.

12.
Gallivan MVE, Lokich JJ: Carcinocythemia (carcinoma cell leukemia): Report of two cases with English literature review. Cancer 53:1100, 1984.

13.
Westerman MP: Bone marrow needle biopsy: An evaluation and critique. Semin Hematol 18:293, 1981.

14.
Garrett TJ, Gee TS, Lieberman PH, et al: The role of bone marrow aspiration and biopsy in detecting marrow involvement by nonhematologic malignancies. Cancer 38:2401, 1976.

15.
Kiely JM, Silverstein MN: Metastatic carcinoma simulating agnogenic myeloid metaplasia and myelofibrosis. Cancer 24:1041, 1969.

16.
Broghamer WL Jr, Keeling MM: The bone marrow biopsy, osteoscan and peripheral blood in nonhematopoietic cancer. Cancer 40:836, 1977.

17.
Steiner RM, Mitchell DG, Rao VM: MRI of diffuse bone marrow disease. Radiol Clin North Am 31:383, 1993.

18.
Bollow M, Knauf W, Korfel A, et al: Initial experience with dynamic MR imaging in evaluation of normal bone marrow versus malignant bone marrow infiltration in humans. J Magn Reson Imaging 7:240, 1997.

19.
Seto T, Imamura F, Kuriyama K, et al: Effect on prognosis of bone marrow infiltration detected by magnetic resonance imaging in small cell lung cancer. Eur J Cancer 33:2333, 1997.

20.
Coustan-Smith E, Behm FG, Sanchez J, et al: Immunological detection of minimal residual disease in children with acute lymphoblastic leukaemia. Lancet 351:550, 1998.

21.
Byard RW, Bormanis J, Jones TG: Leukoerythroblastosis: A much maligned phenomenon (editorial). CMAJ 1137:191, 1987.

22.
Simon D, Gallambos JT: Leukoerythroblastosis with blasts in a patient with alcoholic hepatitis. J Clin Gastroenterol 9:217, 1987.

23.
Chosner JM, Gozzard DJ: Ulcerative colitis complicated by a leukoerythroblastic anaemia. Postgrad Med J 58:662, 1982.

24.
Kubanek B, Heimpel H, Paar G, et al: Hämatologische Veränderungen bei Anorexia Nervosa. Blut 35:115, 1977.

25.
Powsner RA, Zietman AL, Foss FM: Bone marrow suppression after strontium-89 therapy and local radiation therapy in patients with diffuse marrow involvement. Clin Nucl Med 22:147, 1997.

26.
Oster W, Herrmann F, Gamm H, et al: Erythropoietin for the treatment of anemia of malignancy associated with neoplastic bone marrow infiltration. J Clin Oncol 8:956, 1990.

27.
Shamdas GJ, Ahmann FR, Matzner MB, Ritchie JM: Leukoerythroblastic anemia in metastatic prostate cancer: Clinical and prognostic significance in patients with hormone-refractory disease. Cancer 71:3594, 1993.
Books@Ovid
Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology

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3 comments on “CHAPTER 40 ANEMIA ASSOCIATED WITH MARROW INFILTRATION

  1. Best medical article, i ve ever read

  2. Dois dias atrás eu entrei Do-Siga Blog depois de ler um artigo postado aqui na Triond. Vimax Estou tão feliz que eu. Vimax Depois de apenas postando apenas alguns links eu ganhei cerca de 100 mais vistas, e elas continuam chegando. Melhor do que eu recebi mais comentários de pessoas fora da comunidade Triond. Vimax, Vimax. VigRX Plus

  3. thank you for the detailed explanation,, where can i see the tables and the pictures especially the fig. 40-1? thank you so much!

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