Isolated Hemolytic Anemia: An Unusual Manifestation of Occult Malignancy
A 75-year-old female presented complaining of progressive fatigue and dyspnea over several months. Physical examination was significant only for pallor. Palpable splenomegaly was absent. Laboratory studies showed macrocytic anemia with a hemoglobin of 8.2 g/dL, hematocrit of 25.3%, and mean corpuscular volume of 103.7 fL; these values had been within normal limits one year prior. Her platelet count was 188,000/mL and white blood cell count was 10,000/mL, both normal, as were tests of renal and hepatic function, coagulation, and micronutrient levels including iron, folate, and vitamin B-12. The reticulocyte index was 2.4, but only 1.6 after correction for maturation factor, showing a suboptimal response to anemia. Erythrocyte sedimentation rate was elevated at 94 mm/h. Lactate dehydrogenase was elevated at 549 IU/L (normal range 90-250) and haptoglobin was undetectable, consistent with a hemolytic process. D-dimer was mildly elevated at 1.04 µg/mL, and fibrinogen was within normal limits at 363 mg/dL. A peripheral blood smear contained schistocytes and spherocytes, suggesting hemolysis, and also showed leukoerythroblastosis, with polychromasia, nucleated red blood cells, and immature granulocytes (). DAT was negative on two separate occasions, a cold agglutinin assay was negative, and hemoglobin electrophoresis and serum protein electrophoresis were normal. Flow cytometry found no evidence of paroxysmal nocturnal hemoglobinuria. Abdominal ultrasound showed a sonographically normal spleen. As part of the patient’s workup for anemia, upper endoscopy was performed and found no source of bleeding, but did recover a sessile 10 mm polyp from the gastric fundus, which was found to contain a microscopic focus of adenocarcinoma. A bone marrow biopsy revealed poorly differentiated signet ring adenocarcinoma, raising concern for a metastatic gastric cancer (). At this point cytotoxic therapy with capecitabine was initiated. The patient’s anemia continued to worsen, requiring several red blood cell transfusions, and she was given darbepoetin alfa to promote erythropoiesis. She developed an indirect hyperbilirubinemia of 2.7 mg/dL, while maintaining normal platelet counts and appropriate reticulocytosis, with a corrected reticulocyte index as high as 8.4. However, her anemia did not improve. A six-week trial of corticosteroids, given as empiric treatment for possible DAT-negative AIHA, similarly produced no improvement in anemia or in laboratory markers of hemolysis.\nAfter starting treatment for presumed gastric cancer, a palpable breast mass was discovered. Biopsy revealed signet ring adenocarcinoma that was histologically similar to both bone marrow and gastric polyp findings, with strong estrogen receptor positivity (). Additional immunohistochemical staining of the initial bone marrow sample was performed at this time, and was positive for estrogen receptor, E-cadherin, and GATA-3, consistent with primary breast cancer. PET-CT imaging showed diffusely mottled osseous structures consistent with an infiltrative process, but no other metastatic foci. In light of these findings, corticosteroids and chemotherapy were stopped and aromatase inhibition with anastrozole was initiated. This was followed by a rapid improvement in anemia, allowing blood transfusions and darbepoetin alfa treatments to be stopped. The patient survived 28 months from initial presentation with no evidence of recurrent hemolysis, before succumbing to progression of breast cancer.