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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
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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.
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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).
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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 disease19,20,21 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
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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.