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CHAPTER 45 primary process of metastasis and occurs often as a result of loss of
E-cadherin. E-cadherin is a calcium-dependent cell adhesion molecule
ANEMIA ASSOCIATED WITH that likely plays a role in intercellular adhesion and inhibition of inva-
sion by neoplastic cells. The loss of E-cadherin can be caused by many
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MARROW INFILTRATION mechanisms, including mutations and gene silencing. 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. Many members of the
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Vishnu VB Reddy and Josef T. Prchal family of matrix metalloproteinases can also participate in the process
of tumor cell invasion. Stromal cells, such as tumor-associated macro-
phages, and growth factors secreted by them, such as fibroblast growth
factor, are also known to promote tumor spread. 5
SUMMARY Table 45–1 lists the most common causes of extensive cellu-
lar infiltration of marrow. In myelofibrotic disorders of both primary
Myelophthisic anemia is caused by marrow infiltration, typically by metastatic and secondary origin, the fibrosis/osteosclerosis-restricts the available
cancer, and by any nonhematopoietic conditions, for example, granulomatous marrow space and disrupts marrow architecture (Chap. 86). The dis-
inflammation or fibrosis. It can present with an overt leukoerythroblastic ruption may cause cytopenias with production of deformed red cells,
picture or with only a few teardrop-shaped red cells on a blood film. These especially poikilocytes and teardrop-shaped cells, and premature
changes may represent an early spread of the tumor (or other nonhematopoi- release of erythroblasts, myelocytes, and giant platelets. The leukocyte
etic tissue) to the marrow or may indicate massive replacement of the marrow count also may be elevated. Similar abnormalities following marrow
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space. The diagnosis can be made by standard marrow biopsy. Radioisotope replacement by calcium oxalate crystals have been reported. Anemia
scanning and magnetic resonance imaging, although not very sensitive, can seen in metastatic cancer most frequently results from cytokine release
leading to anemia of chronic inflammation (Chap. 37), iron deficiency
be helpful in locating the biopsy site and can also help in estimating the per- as a result of gastrointestinal or uterine bleeding (Chap. 42), or other
centage of involvement of the marrow space. nutritional deficiencies (Chaps. 41 and 44). However, marrow replace-
ment 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
DEFINITION AND HISTORY the marrow, 7–11 but the most common are cancers of the lung, breast,
and prostate. Metastatic foci in the marrow can be found in 20 to 30
Myelophthisic anemia is the term that has been used to describe diverse percent of patients with small cell carcinoma of the lung at the time of
pathologic processes, including Fanconi anemia, but currently refers diagnosis, and in more than 50 percent of patients at autopsy. 12,13 Overt
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to anemia resulting from the presence of spotty to massive marrow leukoerythroblastic blood picture is less common, and its absence is not
infiltration with abnormal cells or tissue components. Strictly speak- a reliable indicator that the marrow is not involved.
ing, the blasts of acute leukemia, plasma cells of myeloma, and cells of The characteristic abnormalities observed in patients with myelo-
lymphoma, chronic leukemia, and myeloproliferative neoplasms fit this phthisic anemia may result partly from an attempt for compensatory
definition. However, the term myelophthisic anemia is best reserved for extramedullary blood formation that generally reflects extramedul-
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marrow replacement by nonhematologic tumors and nonhematopoietic lary hematopoiesis predominantly from the spleen. A similar picture
tissue. Minimal to moderate involvement usually does not cause symp- can be seen when the marrow is replaced by numerous granulomas, 14,15
toms or hematologic changes. Such infiltration is clinically significant, for example, sarcoidosis, disseminated tuberculosis, fungal infections,
however, because in patients with an established diagnosis of cancer, it or by macrophages containing indigestible lipids, as in Gaucher and
indicates metastatic dissemination of the tumor and usually an advanced Niemann-Pick diseases (Chap. 72) and in macrophage activation syn-
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stage. Although extensive infiltration may lead to anemia or even pan- drome (MAS).
cytopenia, anemia can be frequently accompanied by an elevated leu- Marrow necrosis can be an underlying cause of myelophthisic
kocyte count, often with immature myeloid cells in the blood. Platelets anemia. The morphologic picture, best observed in hematoxylin-and-
can be increased, decreased, or normal (megakaryocytic fragments eosin–stained biopsy of marrow, consists of cell debris and occasional
are seen occasionally in the blood film). The findings accompanied by necrotic cells in an eosinophilic amorphus background (Fig. 45–1).
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teardrop-shaped red cells (dacrocytes), prematurely released nucleated Marrow necrosis is generally considered to be very uncommon,
red cells, and immature myeloid cells is referred to as leukoerythroblastic accounting for less than 1 percent of marrow biopsies. Metastatic
reaction (Chaps. 2, 31, and 86), which generally reflects marrow replace- tumors, acute lymphoblastic leukemia (children), and septicemia are
ment by tumor or extramedullary hematopoiesis. generally the underlying cause, 17,18 but sickle cell disease 19–21 and arsenic
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therapy in acute promyelocytic leukemia are other causes. Necrotic
ETIOLOGY AND PATHOGENESIS foci range from small to very extensive (<5 to 90 percent of the biopsy
volume). Extensive necrosis often results in inability to perform flow
Tumor metastasis results from the complex interactions between the cytometry/molecular analysis satisfactorily. A repeat biopsy at a differ-
tumor cells and the surrounding microenvironment. Invasion is the ent site may be needed. 17,23,24
Because myelophthisic anemia is so uncommon, only a few rig-
orous studies of the pathogenesis of anemia in this entity have been
99m
Acronyms and Abbreviations: MRI, magnetic resonance imaging; Tc, a radio- conducted. In vitro study of hematopoietic progenitors reveals only a
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isotope of technetium; Tc sestamibi, a radioisotope of technetium attached to the moderate decrease of their proportion and proliferative capacity. Sim-
99m
sestamibi molecule. ilar reports of erythropoiesis quantitation by ferrokinetic studies reveal
only a moderate defect (Chap. 32). The following confounding factors
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