Hematologic Manifestations of Solid Tumors

Anemia

The most common hematologic manifestation of cancer is anemia; anywhere from 30% to 90% of patients with cancer have documented anemia before the initiation of any treatment. Anemia may be the first presentation of malignancy; for instance, anemia is frequently noted in patients with colon cancer and more frequent in advanced stage disease. The pathogenesis of cancer-related anemia is multifactorial, and can arise from direct cancer tissue invasion with resultant blood loss, tumor involvement of the bone marrow, or hemolysis; it can be a direct effect of chemotherapy or radiation therapy, be associated with chronic renal dysfunction secondary to the malignancy or treatment, among other causes. These causes can be generally divided according to the pathogenesis of the anemia: that resulting from direct blood loss, anemia caused by erythrocyte destruction, and anemia caused by a hypoproliferative marrow state.

A number of cancer-specific mechanisms can be responsible for a hypoproliferative state, including nutritional deficiencies, decreased erythropoietin (EPO) production because of acute or chronic kidney injury, and injury to the bone marrow itself. The most common nutritional abnormality in cancer-related anemia is iron deficiency; roughly 40% of cancer patients may have iron-deficiency, which can be secondary to poor oral intake, as well as from blood loss, commonly seen in gastrointestinal and gynecologic malignancies. Compounding any deficiency in total body iron stores are the myelosuppressive effects on erythropoiesis and iron homeostasis that may result from cancer-associated inflammation and cytokine activation. Many cancers are associated with a systemic inflammatory state, manifested by elevated levels of inflammatory cytokines such as IL-2 and IL-6, which can directly inhibit erythropoiesis and also suppress the amount of iron available for erythropoiesis.

Various systemic mediators of anemia are disrupted in malignancy. When serum EPO concentrations are measured among cancer patients, these levels are inappropriately low in comparison to patients without malignancy but who have the same degree of anemia caused by iron deficiency. Cancer patients also often demonstrate increased levels of hepcidin, a protein critical to iron homeostasis, which acts by decreasing the binding to and breaking down of the iron transporter ferroportin. This subsequently results in increased storage of iron in the form of ferritin, and at the same time decreases free iron that would be used in erythropoiesis. In contrast to iron deficiency, vitamin B ₁₂ deficiency is less frequently observed in patients with anemia and cancer, seen in only 5% to 10% of patients.

Many chemotherapeutic agents have hematologic sequelae; patients undergoing treatment may experience varying degrees of anemia resulting from chemotherapy-induced bone marrow suppression. The European Cancer Anaemia Survey prospectively studied over 15,000 patients with a variety of solid tumors undergoing treatment. Before therapy, 10% of patients had hemoglobin levels below 10 g/dL, and during therapy this increased to almost 40% of patients and was correlated with a worsening performance status. In the same study, radiation therapy alone had less impact on the incidence of anemia, but the combination of chemotherapy and radiation led to a greater degree of anemia than chemotherapy alone. Anemia caused by chemotherapy is related to the cumulative dose, combination of chemotherapeutic agents, and dose schedule. For example, in the treatment of lung cancer with cisplatin and paclitaxel, anemia worsens with an increasing total dose of cisplatin, or if paclitaxel is given over a 24-hour period rather than shorter courses.

Anemia in cancer patients can also occur in the setting of red cell destruction, such as is seen in autoimmune hemolytic anemia, or in the setting of microangiopathic hemolytic anemia (MAHA), which is associated with concurrent thrombocytopenia. Although the true incidence of MAHA among cancer patients is difficult to determine, it is a well-defined entity that has been described in a small (perhaps <10%) subset of cancers, particularly mucin-producing disseminated adenocarcinomas. It is important to distinguish secondary thrombotic microangiopathies (TMAs), which can occur in patients with malignancy, from thrombotic thrombocytopenic purpura (TTP), given the marked differences in underlying pathophysiology. TTP is the result of congenital or acquired absence or inhibition of the von Willebrand cleaving enzyme called “A Disintegrin And Metalloproteinase with Thrombospondin Motifs-13” (ADAMTS13). In contrast, secondary TMAs may have a slight decrease in ADAMTS13 activity, but do not have the severe deficiency of ADAMTS13 activity, typically characterized by a level of less than 10%, that is seen in TTP. Accordingly, patients with secondary TMAs typically have a poor response to therapeutic plasma exchange. Cancer-associated TMAs may arise from direct endothelial damage rather than diminished ADAMTS13 activity. Cancer patients may also develop a MAHA related to the specific medications used during treatment, including cyclosporine, mitomycin, and gemcitabine, and agents inhibiting vascular endothelial growth factor (anti-VEGF) signaling. (See box on Management of Cancer-Related Anemia .)

Erythrocytosis

Outside of patients with myeloproliferative neoplasms, and specifically polycythemia vera, erythrocytosis is an uncommon manifestation of cancer. Polycythemia vera, and other myeloproliferative neoplasms, are typified by acquisition of somatic mutations that upregulate the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway, most commonly via the JAK2 V617F mutation, and phenotypically present as an expansion of myeloid-origin cells, with an elevated hemoglobin and suppressed EPO levels. In these cancers, erythrocytosis is caused by primary expansion of the malignant clone. For such patients, various therapeutic interventions may be considered, including therapeutic phlebotomy or hydroxyurea (see Chapter 70 , The Polycythemias). In solid tumors, erythrocytosis is an uncommon paraneoplastic phenomenon. Paraneoplastic erythropoiesis has been described in several tumors, including renal cell carcinoma. In some instances, there may be association with a common predisposing condition; for instance, patients with von Hippel-Lindau disease are at risk for renal and central nervous system tumors, and the mechanism of erythrocytosis is typically through paraneoplastic EPO expression. Nonetheless, elevated RBC counts are rare in patients with malignancy, particularly those receiving chemotherapy, and usually do not require intervention.

Thrombocytopenia

Chemotherapy and immunosuppressive agents are the most common causes of thrombocytopenia in the cancer patient. For instance, patients receiving cisplatin/gemcitabine for bladder cancer or carboplatin/gemcitabine for lung cancer have rates of clinically significant thrombocytopenia of 30% to 60%. Among patients with hematologic malignancy, thrombocytopenia is even more common, particularly with induction or conditioning chemotherapy regimens. The typical mechanism by which chemotherapy causes thrombocytopenia is through marrow suppression; although, some agents are also associated with immune-mediated thrombocytopenia, and thrombocytopenia may also occur as a sequelae of other processes such as MAHA or TMA (above). Immune thrombocytopenia is typically characterized by a sudden and isolated drop in platelet count shortly after drug administration. Several chemotherapeutics, including gemtuzumab, trastuzumab, and oxaliplatin, have been associated with immune-mediated thrombocytopenia, potentially related to the presence of drug-dependent antibodies.

Thrombocytopenia may also be a result of bone marrow infiltration by tumor cells, thrombotic microangiopathy, consumptive coagulopathy, or as an autoimmune manifestation of the malignancy itself. Bone marrow involvement, often occult, is more common in prostate, lung, and breast cancer; such patients typically have multiple cell lines involved, and may display a leukoerythroblastic appearance on the peripheral smear. Associated laboratory features of disseminated intravascular coagulation (DIC), including an elevated D-dimer and fibrinogen degradation products, can be seen in cancer patients, and are more common with advanced disease. (See box on Management of Cancer-Related Thrombocytopenia .)