Chapter 45: Anemia Associated with Marrow Infiltration

Myelophthisic anemia is the term that has been used to describe diverse pathologic processes, including Fanconi anemia,¹ but currently refers to anemia resulting from the presence of spotty to massive marrow infiltration with abnormal cells or tissue components. Strictly speaking, the blasts of acute leukemia, plasma cells of myeloma, and cells of lymphoma, chronic leukemia, and myeloproliferative neoplasms fit this definition. However, the term myelophthisic anemia² is best reserved for marrow replacement by nonhematologic tumors and nonhematopoietic tissue. Minimal to moderate involvement usually does not cause symptoms or hematologic changes. Such infiltration is clinically significant, however, because in patients with an established diagnosis of cancer, it indicates metastatic dissemination of the tumor and usually an advanced stage. Although extensive infiltration may lead to anemia or even pancytopenia, anemia can be frequently accompanied by an elevated leukocyte count, often with immature myeloid cells in the blood. Platelets can be increased, decreased, or normal (megakaryocytic fragments are seen occasionally in the blood film). The findings accompanied by teardrop-shaped red cells (dacrocytes), prematurely released nucleated red cells, and immature myeloid cells is referred to as leukoerythroblastic reaction (Chaps. 2, 31, and 86), which generally reflects marrow replacement by tumor or extramedullary hematopoiesis.

Tumor metastasis results from the complex interactions between the tumor cells and the surrounding microenvironment. Invasion is the primary process of metastasis and occurs often as a result of loss of E-cadherin. E-cadherin is a calcium-dependent cell adhesion molecule that likely plays a role in intercellular adhesion and inhibition of invasion by neoplastic cells. The loss of E-cadherin can be caused by many mechanisms, including mutations and gene silencing.³ Dysregulation of calcium influx pathways through stromal interaction molecule (STIM) and calcium-permeable transient receptor potential (TRP) also plays a role in tumor invasive and metastatic behavior.⁴ Many members of the family of matrix metalloproteinases can also participate in the process of tumor cell invasion. Stromal cells, such as tumor-associated macrophages, and growth factors secreted by them, such as fibroblast growth factor, are also known to promote tumor spread.⁵

Table 45–1 lists the most common causes of extensive cellular infiltration of marrow. In myelofibrotic disorders of both primary and secondary origin, the fibrosis/osteosclerosis-restricts the available marrow space and disrupts marrow architecture (Chap. 86). The disruption may cause cytopenias with production of deformed red cells, especially poikilocytes and teardrop-shaped cells, and premature release of erythroblasts, myelocytes, and giant platelets. The leukocyte count also may be elevated. Similar abnormalities following marrow replacement by calcium oxalate crystals have been reported.⁶ Anemia seen in metastatic cancer most frequently results from cytokine release leading to anemia of chronic inflammation (Chap. 37), iron deficiency as a result of gastrointestinal or uterine bleeding (Chap. 42), or other nutritional deficiencies (Chaps. 41 and 44). However, marrow replacement causing a myelophthisic anemia as the sole cause of anemia also occurs. The marrow microenvironment is susceptible to implantation of bloodborne malignant cells. Almost all cancers can metastasize to the marrow,^7,8,9,10,11 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 of patients at autopsy.^12,13 Overt leukoerythroblastic blood picture is less common, and its absence is not a reliable indicator that the marrow is not involved.

The characteristic abnormalities observed in patients with myelophthisic anemia may result partly from an attempt for compensatory extramedullary blood formation that generally reflects extramedullary hematopoiesis predominantly from the spleen. A similar picture can be seen when the marrow is replaced by numerous granulomas,^14,15 for example, sarcoidosis, disseminated tuberculosis, fungal infections, or by macrophages containing indigestible lipids, as in Gaucher and Niemann-Pick diseases (Chap. 72)¹⁶ and in macrophage activation syndrome (MAS).

Marrow necrosis can be an underlying cause of myelophthisic anemia. The morphologic picture, best observed in hematoxylin-and-eosin–stained biopsy of marrow, consists of cell debris and occasional necrotic cells in an eosinophilic amorphus background (Fig. 45–1).¹⁷ Marrow necrosis is generally considered to be very uncommon, accounting for less than 1 percent of marrow biopsies. Metastatic tumors, acute lymphoblastic leukemia (children), and septicemia are generally the underlying cause,^17,18 but sickle cell disease^19,20,21 and arsenic therapy in acute promyelocytic leukemia are other causes.²² Necrotic foci range from small to very extensive (<5 to 90 percent of the biopsy volume). Extensive necrosis often results in inability to perform flow cytometry/molecular analysis satisfactorily. A repeat biopsy at a different site may be needed.^17,23,24

Because myelophthisic anemia is so uncommon, only a few rigorous studies of the pathogenesis of anemia in this entity have been conducted. In vitro study of hematopoietic progenitors reveals only a moderate decrease of their proportion and proliferative capacity.²⁵ Similar reports of erythropoiesis quantitation by ferrokinetic studies reveal only a moderate defect (Chap. 32).²⁶ The following confounding factors contribute to anemia: elevated hepcidin (Chap. 37) and other factors, including hematopoiesis-inhibiting cytokines released from tumor cells (Chap. 37) and iron (Chap. 42) and folate and cobalamin (Chap. 41) deficiencies. When they are excluded, the finding discussed above suggests that only massive marrow replacement leads to anemia.

Symptoms and signs associated with infiltrative marrow disorders usually are related to the underlying disease. Other symptoms, such as fatigue, often from upregulated cytokines, may also contribute to anemia itself. Some patients are asymptomatic, and the incidental discovery of cytopenias and leukoerythroblastic blood morphology leads to diagnosis of an underlying disorder

BLOOD

The anemia usually is mild to moderate, but it can be severe. 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 (Chap. 31; Fig. 45–2). The combination of nucleated red cells and immature myeloid precursors constitutes the leukoerythroblastic picture that is characteristic of marrow infiltration and extramedullary hematopoiesis. The presence of cancer cells on the blood film occurs occasionally and always indicates marrow invasion (Fig. 45–3).²⁷

MARROW

Marrow biopsy is the most reliable procedure used to diagnose marrow-infiltrative disease and should be performed in all patients with suspected metastatic carcinoma or hematologic features of myelophthisic anemia. Marrow aspiration^24,28 does not provide a reliable yield of tumor cells and is particularly difficult in primary or secondary myelofibrosis. The inability to aspirate marrow (dry tap) leads to a high degree of suspicion of marrow replacement and accompanying myelofibrosis. Because the diagnostic marrow yield from biopsies depends on the amount of tissue examined, bilateral posterior iliac crest marrow biopsies may be necessary. In patients with metastatic cancer involving the marrow, the blood CD34-positive cell count can be up to 50 times higher than in patients with metastatic cancer without marrow involvement.²⁹

ISOTOPE AND IMAGING PROCEDURES

Technetium-99m (^99mTc) sestamibi uptake reliably identifies marrow infiltration by Gaucher cells. Sestamibi is a pharmaceutical agent used in nuclear medicine imaging. Magnetic resonance imaging (MRI) is also helpful for defining the severity of marrow replacement and is being used with increasing frequency. This imaging approach is especially useful for following resolution of marrow infiltration in patients with type 1 Gaucher disease who are treated with enzyme-replacement therapy.^20,30,31 An isotopic bone scan or MRI study showing focal accumulation of radioactive tracers can be helpful in locating a suitable site for biopsy,^20,32 but a negative study of the area does not exclude the possibility of marrow involvement. On MRI, marrow necrosis characteristically has an extensive, diffuse, geographic pattern of signal abnormality consisting of a central area of variable signal intensity surrounded by a distinct peripheral enhancing rim.²¹

The cause of a leukoerythroblastic blood picture is known to occur in a patient with metastatic cancer or overt hematologic malignancy. In the absence of a likely cause after clinical evaluation, the initial approach to diagnosis is the marrow biopsy. Although it is not a very sensitive technique, with the help of immunocytochemistry and flow cytometry for tumor-specific antigens, its diagnostic sensitivity and specificity increases. MRI or isotopic scanning before the marrow may aid in locating the site of the biopsy. Hematologic disorders causing marrow fibrosis, notably primary myelofibrosis, may mimic a myelophthisic disorder, but the distinctions are usually evident. For example, the patient with primary myelofibrosis invariably has splenic enlargement and the patient with metastatic cancer nearly always does not (Chap. 91). If the myelophthisis is the result of a storage disease or other infiltrative cause, the appropriate chemical tests, as well as marrow biopsy, are helpful in diagnosis. Nucleated red cells and leukocytosis can be seen in acute conditions, including overwhelming sepsis, acute severe hypoxia, postcardiac arrest, and chronic conditions such as thalassemia major, congestive heart failure, and severe hemolytic anemia.

The goal of treatment is managing the underlying disease. Patients with marrow infiltration caused by cancer should be treated appropriately; however, in some instances the presence of marrow infiltration may not adversely affect the outcome. If treatment is successful, not only the malignant cells but also the reactive fibrosis surrounding metastatic foci may completely disappear. In hormone-refractory prostate cancer, the presence of a leukoerythroblastic picture does not seem to influence survival.³³ However, in most patients with cancers metastatic to the marrow, only short-term survival is a rule.