AUTOIMMUNE ASSOCIATED
DANIEL
CANALE,
ROBERT
FELDMAN,
MICHAEL MARVIN
ROSEN,
HEMOLYTIC WITH
ANEMIA
SEMINOMA
M.D. M.D. M.D.
B. HARVARD,
M.D.
From the Departments of Laboratory Medicine, Urology, and Internal Medicine, Yale University School of Medicine, New Haven. Connecticut
ABSTRACT - The first case report of seminoma of the testis associated with autoimmune hemolytic anemia is presented. Additional unusual manifestations of the seminoma in this patient included a diffuse osteosclerosis due to metastatic bony involvement and prompt abatement of the hemolysis following splenectomy. The association of epithelial neoplasms with autoimmune hemolytic anemia is discussed.
Since the application by Boorman, Dodd, and Loutit in 1946l of the direct antiglobulin test to the study of hemolytic anemias, numerous examples of an association between autoimmune hemolytic anemia and neoplasia have been documented. The vast majority have occurred in lymphoma and myeloproliferative disease. There has also been an infrequent association with epithelial neoplasm. We describe what we believe to be the first reported case of Coombs’ positive hemolytic anemia associated with seminoma of the testis. Case Report A thirty-four-year-old white man was admitted to Yale-New Haven Hospital for evaluation of anemia and a swollen right testis. The patient stated that for the preceding several months friends had noted increasing pallor. The week prior to admission he experienced dizziness and occasional nausea. He stated that he had recently noted an increase in the size ofhis right testis. The remainder of his history was noncontributory. Physical examination revealed a tall, obese, chronically ill appearing man with normal vital signs. The conjunctiva, mucous membranes, and nail bed exhibited marked pallor. The lower
UROLOGY
i
MARCH 1975 / VOLUME
V, NUMBER
3
border of the spleen was palpated at the iliac crest, The liver edge was felt 5 fingerbreadths below the right costal margin. The entire scrotum was enlarged and transilluminated. A small left hydrocele was present. The right hemiscrotum was approximately two times normal size, and the testicle was hard, irregular, and adherent to the medial scrotal fascia. The initial hematocrit was 17.6 with a mean corpuscular volume of97 cu. micra. mean corpuscular hemoglobin of 99.9 picograms, and mean corpuscular hemoglobin concentration of29.3 per cent. White blood cell count was 6,600 with 28 per cent segmented neutrophils, 67 per cent lymphocytes, and 5 per cent monocytes. Platelet count was 140,000. The peripheral smear revealed slight macrocytosis, moderate anisocytosis and frequent schistocytes. and poikilocytosis, Reticulocyte count varied from 3.5 to 7.7 pei cent. A direct Coombs’ test was 3 plus. Heat eluate preparation of the antibody showed nonspecificity. The serum iron was 76 micrograms per 100 ml. with iron-binding capacity of 256 micrograms per 100 ml. Hemoglobin electrophoresis revealed predominance of type AA with normal levels of Aa. Serum haptoglobin was at the lower limits of normal. A sugar-water test and test for Donath-Landsteiner antibodv were
111
negative. A slight increase in osmotic fragility was noted, both in the fresh state and after incubation. Plasma B12 and red blood cell folate were normal. Erythrocyte glucose-6-phosphate dehydrogenase was normal as was the leukocyte alkaline phosphatase score. Glucose, blood urea nitrogen, creatinine, uric acid, electrolytes, bilirubin, serum glutamic oxaloacetic transaminase, alkaline phosphatase, acid phosphatase, amylase, and lipase were all within normal limits. Total protein was 6 Gm. per 100 ml. with 3.3 Gm. of albumin. Immunoelectrophoresis of the patient’s serum demonstrated slightly decreased levels of immunoglobulins A and M with a normal G. Aspirated fluid from the right hydrocele showed no malignant cells. Chest roentgenogram showed diffuse marked sclerosis of all bones visualized. Intravenous pyelogram revealed downward displacement of the left kidney by the spleen and lateral displacement of the right kidney. Lymphangiography demonstrated enlarged nodes with features characteristic of metastatic involvement in the paralumbar and ascending iliac nodes. On the sixth hospital day the patient underwent right orchiectomy. The right testis weighed 200 Gm. and was almost totally replaced by seminoma (Fig. 1A and B). The tumor did not extend beyond the tunica albuginea nor invade the epididymis or vas deferens. A bone marrow biopsy was obtained at the same time (Fig. 1C). It displayed marked hypercellularity and moderate enlargement of the bony trabeculae, an increase in both myeloid and erythroid precursors as well as a marked increase in the number of lymphocytes. In addition, the marrow was filled with metastatic seminoma cells surrounded in most places by lymphocytes. Postoperatively the patient was given 100 mg. prednisone per day but hemolysis continued, requiring up to 2 units of packed red blood cells per day to sustain his hematocrit in the low 30s. The enlarged spleen was believed to be playing a major role in destruction of red blood cells, therefore, splenic irradiation with a total of 1,200 rads administered in four doses was begun on the eighteenth hospital day. Intravenous treatment with cyclophosphamide (Cytoxan 1 Gm./m’) followed by vincristine (2.2 mg.) was begun on the eighteenth hospital day. The patient was discharged on the nineteenth hospital day with a hematocrit of 27.5. Because of persistent hemolysis, the patient was readmitted for splenectomy two months after
412
discharge. A 1,488-G m. spleen with multiple accessory spleens was removed. Microscopically, the spleen demonstrated extramedullary hematopoiesis and passive congestion. One week after splenectomy hematocrit was 34, and the reticulocyte count was 7.5. Steroids were discontinued. Over the next month, the patient’s hematocrit rose to 43.6 and has remained stable since. A repeat bone marrow aspiration was performed one month after splenectomy which revealed a decrease in the hypercellularity and diminution of the lymphocytes. No tumor cells were seen. The patient is now approximately fifteen months postsplenectomy and remains symptom free. His hematocrit has now been stable for fourteen months ranging between 42 and 50. He continues to receive weekly injections of vincristine and has no evidence of tumor recurrence.
Comment As reviewed recently by Miura et al2 autoimmune hemolytic anemia associated with malignant conditions other than the lymphoproliferative and myeloproliferative diseases is relatively uncommon. Pirofsky3 identified only 20 such patients in 234 cases of autoimmune hemolytic anemia. These nonhematopoietic neoplasms have been epithelial with the exception of cases of Kaposi’s sarcoma and ovarian teratoma. Included among these have been cancers of the breast, cervix, colon, kidney, larynx, lung, skin (including melanoma), and uterus.2’3 As far as we could determine, besides being the first reported association between seminoma and autoimmune hemolytic anemia, this case presented two other interesting features. First, the pattern of osseous response was quite unusual. Seminomas infrequently metastasize to bone; and when they do, the lesions are typically osteolytic and form discrete tumor masses.4 Osteoblastic metastases have been reported but were localized lesions.5 In contrast, diffuse osteosclerosis was present in this patient, and the seminoma dispersed diffusely cells were throughout the marrow. The second interesting feature of this case was the prompt abatement of hemolysis following splenectomy. In addition to its more important role of sequestration of cells coated by and/or damaged by antibody, the spleen is itself a source of antibody formation in autoimmune hemolytic anemia. 6 Thrombocytopenia and leukopenia were not present at the time of splenectomy in the
UROLOGY
/ MARCH 1975 / VOLUME
V, NUMBER 3
FIGURE 1. (A) Mecliu m-power ciezr of‘te.vtic~ /at- tumor .showing replucement of nomd pc~rr~r~chym by .sheet of typical seminomrl cells containing focal accumulations of 1ymphocyte.q x 100). (B) Nigh-power view of tumor cci1.v rerding characteri.stic prominent nucleoli in round I-P siculnr nuclei surrounded by pale, u,xt~~y cytoplasm (X 400). iC) Low-power r;im of bonc~ marrow biopsy revealing murked hcyrx?rcellularity and hypertrophy of bony tmheculne ( x 2~ ). (Hemclto.r!ylin and eosin stuin. )
face of the markedly shortened survival of red blood cells; thus it appears unlikely that sequestration alone was responsible for this shortened survival. Considering the known tendency of seminomas to provoke a lymphoid response, at times so brisk as to mimic lymphoma,4 and the known association of reticuloendothelial cell hyperplasia and autoimmune hemolytic anemia, it is perhaps surprising that this type anemia associated with seminoma has not been observed previously. Department New
414
of Laboratory Medicine 333 Cedar Street Haven, Connecticut 06504 (DR. CANALE)
References 1. BOORMAN, K. E., DODD, B. E., and LOUTIT, J. F.: Hemolytic icterus (acholuric jaundice) congenital and acquired, Lancet 1: 812 (1946). 2. MIURA, A. B., et al.: Autoimmune hemolytic anemia associated with colon cancer, Cancer 33: 111 (1974). 3. PIROFSKY, B.: Autoimmunization and the Autoimmune Hemolytic Anemias, Baltimore, Williams and Wilkins Co., Inc., 1969, pp. 229-261. 4. JOHNSON, D. E.: Testicular Tumors, New York, Medical Examination Publishing Co., Inc., 1972, pp. 7, 50. 5. SUM, P. W., ROSWITT, B., and UNCER, S. M.: Skeletal metastases from malignant testicular tumors, Am. J. Roentgenol. 83: 704 (1960). 6. DACIE, J. V., and WORLLEDGE, S. M.: Auto-immune hemolytic anemias, Prog. Hematol. 6: 82 (1969). 7. DACIE, J. V,: The Hemolytic Anaemias, New York, Grune and Stratton Inc., 1967, p. 791.
UROLOGY
/ MARCH 1975 / VOLUME V, NUMBER 3
DANIEL
CANALE,
ROBERT
FELDMAN,
MICHAEL MARVIN
ROSEN,
HEMOLYTIC WITH
ANEMIA
SEMINOMA
M.D. M.D. M.D.
B. HARVARD,
M.D.
From the Departments of Laboratory Medicine, Urology, and Internal Medicine, Yale University School of Medicine, New Haven. Connecticut
ABSTRACT - The first case report of seminoma of the testis associated with autoimmune hemolytic anemia is presented. Additional unusual manifestations of the seminoma in this patient included a diffuse osteosclerosis due to metastatic bony involvement and prompt abatement of the hemolysis following splenectomy. The association of epithelial neoplasms with autoimmune hemolytic anemia is discussed.
Since the application by Boorman, Dodd, and Loutit in 1946l of the direct antiglobulin test to the study of hemolytic anemias, numerous examples of an association between autoimmune hemolytic anemia and neoplasia have been documented. The vast majority have occurred in lymphoma and myeloproliferative disease. There has also been an infrequent association with epithelial neoplasm. We describe what we believe to be the first reported case of Coombs’ positive hemolytic anemia associated with seminoma of the testis. Case Report A thirty-four-year-old white man was admitted to Yale-New Haven Hospital for evaluation of anemia and a swollen right testis. The patient stated that for the preceding several months friends had noted increasing pallor. The week prior to admission he experienced dizziness and occasional nausea. He stated that he had recently noted an increase in the size ofhis right testis. The remainder of his history was noncontributory. Physical examination revealed a tall, obese, chronically ill appearing man with normal vital signs. The conjunctiva, mucous membranes, and nail bed exhibited marked pallor. The lower
UROLOGY
i
MARCH 1975 / VOLUME
V, NUMBER
3
border of the spleen was palpated at the iliac crest, The liver edge was felt 5 fingerbreadths below the right costal margin. The entire scrotum was enlarged and transilluminated. A small left hydrocele was present. The right hemiscrotum was approximately two times normal size, and the testicle was hard, irregular, and adherent to the medial scrotal fascia. The initial hematocrit was 17.6 with a mean corpuscular volume of97 cu. micra. mean corpuscular hemoglobin of 99.9 picograms, and mean corpuscular hemoglobin concentration of29.3 per cent. White blood cell count was 6,600 with 28 per cent segmented neutrophils, 67 per cent lymphocytes, and 5 per cent monocytes. Platelet count was 140,000. The peripheral smear revealed slight macrocytosis, moderate anisocytosis and frequent schistocytes. and poikilocytosis, Reticulocyte count varied from 3.5 to 7.7 pei cent. A direct Coombs’ test was 3 plus. Heat eluate preparation of the antibody showed nonspecificity. The serum iron was 76 micrograms per 100 ml. with iron-binding capacity of 256 micrograms per 100 ml. Hemoglobin electrophoresis revealed predominance of type AA with normal levels of Aa. Serum haptoglobin was at the lower limits of normal. A sugar-water test and test for Donath-Landsteiner antibodv were
111
negative. A slight increase in osmotic fragility was noted, both in the fresh state and after incubation. Plasma B12 and red blood cell folate were normal. Erythrocyte glucose-6-phosphate dehydrogenase was normal as was the leukocyte alkaline phosphatase score. Glucose, blood urea nitrogen, creatinine, uric acid, electrolytes, bilirubin, serum glutamic oxaloacetic transaminase, alkaline phosphatase, acid phosphatase, amylase, and lipase were all within normal limits. Total protein was 6 Gm. per 100 ml. with 3.3 Gm. of albumin. Immunoelectrophoresis of the patient’s serum demonstrated slightly decreased levels of immunoglobulins A and M with a normal G. Aspirated fluid from the right hydrocele showed no malignant cells. Chest roentgenogram showed diffuse marked sclerosis of all bones visualized. Intravenous pyelogram revealed downward displacement of the left kidney by the spleen and lateral displacement of the right kidney. Lymphangiography demonstrated enlarged nodes with features characteristic of metastatic involvement in the paralumbar and ascending iliac nodes. On the sixth hospital day the patient underwent right orchiectomy. The right testis weighed 200 Gm. and was almost totally replaced by seminoma (Fig. 1A and B). The tumor did not extend beyond the tunica albuginea nor invade the epididymis or vas deferens. A bone marrow biopsy was obtained at the same time (Fig. 1C). It displayed marked hypercellularity and moderate enlargement of the bony trabeculae, an increase in both myeloid and erythroid precursors as well as a marked increase in the number of lymphocytes. In addition, the marrow was filled with metastatic seminoma cells surrounded in most places by lymphocytes. Postoperatively the patient was given 100 mg. prednisone per day but hemolysis continued, requiring up to 2 units of packed red blood cells per day to sustain his hematocrit in the low 30s. The enlarged spleen was believed to be playing a major role in destruction of red blood cells, therefore, splenic irradiation with a total of 1,200 rads administered in four doses was begun on the eighteenth hospital day. Intravenous treatment with cyclophosphamide (Cytoxan 1 Gm./m’) followed by vincristine (2.2 mg.) was begun on the eighteenth hospital day. The patient was discharged on the nineteenth hospital day with a hematocrit of 27.5. Because of persistent hemolysis, the patient was readmitted for splenectomy two months after
412
discharge. A 1,488-G m. spleen with multiple accessory spleens was removed. Microscopically, the spleen demonstrated extramedullary hematopoiesis and passive congestion. One week after splenectomy hematocrit was 34, and the reticulocyte count was 7.5. Steroids were discontinued. Over the next month, the patient’s hematocrit rose to 43.6 and has remained stable since. A repeat bone marrow aspiration was performed one month after splenectomy which revealed a decrease in the hypercellularity and diminution of the lymphocytes. No tumor cells were seen. The patient is now approximately fifteen months postsplenectomy and remains symptom free. His hematocrit has now been stable for fourteen months ranging between 42 and 50. He continues to receive weekly injections of vincristine and has no evidence of tumor recurrence.
Comment As reviewed recently by Miura et al2 autoimmune hemolytic anemia associated with malignant conditions other than the lymphoproliferative and myeloproliferative diseases is relatively uncommon. Pirofsky3 identified only 20 such patients in 234 cases of autoimmune hemolytic anemia. These nonhematopoietic neoplasms have been epithelial with the exception of cases of Kaposi’s sarcoma and ovarian teratoma. Included among these have been cancers of the breast, cervix, colon, kidney, larynx, lung, skin (including melanoma), and uterus.2’3 As far as we could determine, besides being the first reported association between seminoma and autoimmune hemolytic anemia, this case presented two other interesting features. First, the pattern of osseous response was quite unusual. Seminomas infrequently metastasize to bone; and when they do, the lesions are typically osteolytic and form discrete tumor masses.4 Osteoblastic metastases have been reported but were localized lesions.5 In contrast, diffuse osteosclerosis was present in this patient, and the seminoma dispersed diffusely cells were throughout the marrow. The second interesting feature of this case was the prompt abatement of hemolysis following splenectomy. In addition to its more important role of sequestration of cells coated by and/or damaged by antibody, the spleen is itself a source of antibody formation in autoimmune hemolytic anemia. 6 Thrombocytopenia and leukopenia were not present at the time of splenectomy in the
UROLOGY
/ MARCH 1975 / VOLUME
V, NUMBER 3
FIGURE 1. (A) Mecliu m-power ciezr of‘te.vtic~ /at- tumor .showing replucement of nomd pc~rr~r~chym by .sheet of typical seminomrl cells containing focal accumulations of 1ymphocyte.q x 100). (B) Nigh-power view of tumor cci1.v rerding characteri.stic prominent nucleoli in round I-P siculnr nuclei surrounded by pale, u,xt~~y cytoplasm (X 400). iC) Low-power r;im of bonc~ marrow biopsy revealing murked hcyrx?rcellularity and hypertrophy of bony tmheculne ( x 2~ ). (Hemclto.r!ylin and eosin stuin. )
face of the markedly shortened survival of red blood cells; thus it appears unlikely that sequestration alone was responsible for this shortened survival. Considering the known tendency of seminomas to provoke a lymphoid response, at times so brisk as to mimic lymphoma,4 and the known association of reticuloendothelial cell hyperplasia and autoimmune hemolytic anemia, it is perhaps surprising that this type anemia associated with seminoma has not been observed previously. Department New
414
of Laboratory Medicine 333 Cedar Street Haven, Connecticut 06504 (DR. CANALE)
References 1. BOORMAN, K. E., DODD, B. E., and LOUTIT, J. F.: Hemolytic icterus (acholuric jaundice) congenital and acquired, Lancet 1: 812 (1946). 2. MIURA, A. B., et al.: Autoimmune hemolytic anemia associated with colon cancer, Cancer 33: 111 (1974). 3. PIROFSKY, B.: Autoimmunization and the Autoimmune Hemolytic Anemias, Baltimore, Williams and Wilkins Co., Inc., 1969, pp. 229-261. 4. JOHNSON, D. E.: Testicular Tumors, New York, Medical Examination Publishing Co., Inc., 1972, pp. 7, 50. 5. SUM, P. W., ROSWITT, B., and UNCER, S. M.: Skeletal metastases from malignant testicular tumors, Am. J. Roentgenol. 83: 704 (1960). 6. DACIE, J. V., and WORLLEDGE, S. M.: Auto-immune hemolytic anemias, Prog. Hematol. 6: 82 (1969). 7. DACIE, J. V,: The Hemolytic Anaemias, New York, Grune and Stratton Inc., 1967, p. 791.
UROLOGY
/ MARCH 1975 / VOLUME V, NUMBER 3
