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).