Medical and Pediatric Oncology 19:496-498 (1991)
Malignant Thymoma Associated with Peripheral T-cell Lymphocytosis Donald C. Doll, MD, Rodney J. Landreneau, MD, and Alan F. List, MD Three cases of peripheral T-cell lyrnphocytosis associated with thymorna are described. Each patient had a malignant, predominantly lymphocytic thymoma with resolution of lyrnphocytosis upon treatment
of the epithelial neoplasm. These findings suggest that lyrnphocytosis complicating thymorna is a paraneoplastic phenomenon and is not part of the neoplastic process.
Key words: thymic neoplasm, leukocytosis
INTRODUCTION
Thymomas are epithelial neoplasms that may be associated with a variety of paraneoplastic syndromes [ 11. Hematologic abnormalities may be detected in 10% of patients [2] and include red cell aplasia, pancytopenia, and hypogammaglobulinemia [ 1,3]. Lymphocytosis associated with malignant thymoma has been reported rarely [4-71. We describe three cases of peripheral T-cell lymphocytosis associated with malignant thymoma with resolution of hematologic abnormalities upon treatment of the epithelial malignancy. These findings suggest that T-lymphocytosis is a paraneoplastic manifestation of thymoma and is not involved in the neoplastic process.
biopsy diagnosis. There was invasion into adjacent adipose tissue and the phrenic nerve margin was positive for tumor. Immunostaining of the surgical specimen revealed an antigenic profile consistent with thymic cortical lymphocytes (CD-4, CD-8, CD-2, CD-5, CD-7, and CD-9). Three weeks after resection the leukocyte count was 9.9 X lO’/liter with 32% lymphocytes with a normal distribution of lymphocyte subsets. Because of local tumor extension, external beam irradiation (5040 cGy) was administered to the AP and PA of the lung and right and left lateral lung fields. Three months after completion of treatment the absolute lymphocyte count remains in the normal range.
CASE 1
CASE 2
A 77-year-old male was admitted to the hospital for transurethral resection of the prostate. Physical exam revealed prostatic hypertrophy; there was no hepatosplenomegaly or lymphadenopathy. Chest X-ray and computed tomography (CT) of the chest disclosed an 8-cmdiameter mass in the anterior mediastinurn. Hemogram revealed a leukocyte count of 15.7 X 109/literwith 52% mature appearing lymphocytes; hemoglobin, 13.1 g/dl; and platelets, 978 X lO’/liter. Bone marrow aspirate and biopsy were normal with 14% lymphocytes. Immunophenotyping studies of the peripheral blood lymphocytes showed reactivity with pan-T cell antibodies (CD-5, 77%, CD-7, 79%; and CD-2, 83%). CT directed needle biopsy of the mass was nondiagnostic. Mediastinotomy biopsy was performed and histological exam showed a tumor composed predominantly of lymphocytes intermingled with epithelial cells consistent with lymphocytic thymoma. Surgical extirpation of the tumor was done and histologic studies confirmed the 0 1991 Wiley-Liss, Inc.
A 43-year-old male was hospitalized for evaluation of hoarseness and chest pain. Physical exam was normal. Chest X-ray and CT scan revealed an anterior mediastinal mass. Leukocyte count was 18.2 X lO’/liter with 62% small, mature appearing lym hocytes; hemoglobin, 14.7 g/dl; and platelets, 315 X 10! /liter. Immunophenotyping of peripheral lymphocytes disclosed a T-cell lineage (CD-5,73%; CD-7, 72%; and CD-2, 85%). Bone marrow aspiration and biopsy were normal with 19% lymphocytes. Needle biopsy of the tumor was inconclusive and a thoracotomy was performed. A mediastinal
From the Department of Medicine, Veterans Administration Hospital, Columbia, Missouri and Tucson, Arizona, and Department of Surgery, University of Missouri, Columbia, Missouri. Received October 9, 1990; accepted April 12, 1991. Address reprint requests to Dr. Donald C. Doll, Department of Medicine, Veterans Administration Hospital, Columbia, MO 65212.
Peripheral T-cell Lymphocytosis
497
TABLE I. Lymphocytosis Associated With Thymoma
Reference Case 1 Case 2 Case 3 Pedraza [5] Griffin et al. [4] Shachor et al. [6] Soler et al. [7]
Agelsex 77/M 43/M
56lM 69lM 64/F 371F 72lF
Histology thymoma
Absolute lymphocyte count/mm3
T-cell phenotype of peripheral blood
Lyrnphocytic Lymphocytic Lymphocytic Lymphocytic Lymphocytic Lymphocytic Lymphocytic
8164 11284 15028 10500 13156 24360 6200
Cortical thymocytes Cortical thymocytes Suppressor NAB NAa Helper Suppressor
aNA, not available.
mass was found to invade the heart and great vessels precluding surgical resection. Biopsy of the mass revealed lymphocytic thymoma. Five courses of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) were administered with a reduction in tumor size. A thoracotomy was performed and the remaining tumor was excised. Pathologic studies confirmed a thymoma of lymphocytic type with tumorfree margins. Immunophenotypically, the tumor lymphocytes expressed an antigenic pattern of cortical thymocytes (CD-5,60%; CD-7,69%; CD-2,95%). One month postoperatively the leukocyte count was 9.0 X 109/liter with 31% lymphocytes with normal cell marker studies. At 9 months follow-up the blood counts remain normal. CASE 3
A 55-year-old was hospitalized for treatment of pneumonia. A chest radiograph performed after resolution of the pulmonary infiltrates revealed an anterior mediastinal mass. Chest CT demonstrated a 5 X 7 cm thymic mass with extensive pleural deposits. At thoracotomy, diffuse nodular tumor deposits were noted involving the parietal and visceral pleura. Biopsy of the thymic and pleural masses revealed malignant thymoma of lymphocyte predominant type. The patient declined therapy at that time. Fourteen months later the patient returned with progressive chest pain and dyspnea. Chest CT demonstrated further enlargement of the mediastinal mass with confluence of the pleural nodules. The leukocyte count was 28.9 X 109/liter with 52% mature-appearing lymphocytes without azurophilic cytoplasmic granules. Lymphocyte typing disclosed a T-cell lymphocytosis with suppressor T-cell predominance (CD-3; 97%; CD-8, 52%;CD-4, 27%). A bone marrow aspirate and biopsy was unremarkable with 10% lymphocytes. The patient consented to treatment and six monthly courses of cisplatin and doxorubicin were administered with >75% reduction in tumor volume. One year after completion of
therapy the patient is symptom-free with a leukocyte count of 11.O X 109/literwith 32% lymphocytes. Pertinent data for patients with lymphocytosis and thymoma are depicted in Table I. DISCUSSION
These patients presented with a mediastinal mass and absolute lymphocytosis. Subsequent clinical and/or pathologic evaluation showed that each patient had a malignant thymoma, predominantly lymphocytic type, with local and/or pleural extension. Immunophenotypicanalysis of peripheral blood disclosed a T-cell lineage in all cases and in both cases of thymoma when phenotypic studies were performed. Of note, there was normalization of blood counts after completion of treatment of the underlying thymoma. Only four cases of thymoma associated with absolute lymphocytosishave been reported previously [4-7]. Like our cases, the patients harbored a predominantly lymphocytic thymoma, and peripheral T-cell lymphocytosis, and had resolution of the lymphocytosis following treatment. Three of the four cases were malignant [4-61. The pathogenesis of lymphocytosis associated with thymoma is unknown. Shachor et al. [6] suggested that lymphocytosis resulted from spillover of neoplastic helper T-cells derived from the thymic neoplasm. Concordance of the lymphocyte immunophenotypefrom the peripheral blood and thymic tumor in our cases supports the notion of peripheralization of tumor-derived lymphocytes. Our findings and those reported by Soler et al. [7], however, indicate that T-cell phenotype may vary and include either suppressor or helper T-lymphocytes, or an antigenic profile consistent with cortical thymocytes (i.e., CD4 and CD8 positive). Although we cannot exclude a clonal origin of the lymphocytosis, the absence of marrow involvement and resolution with locally directed therapy (e.g., Case 1) suggest that the cells remain under thymic regulation. T-cell receptor gene rearrangement studies would be helpful in future cases [8,9].
498
Doll et al.
In conclusion, absolute peripheral T-cell lymphocytosis may be associated with thymoma. To date all thymoma cases have been of the lymphocytic predominant type and six of the seven cases have been malignant. Additional studies are needed to elucidate the pathogenesis and cell of origin of the lymphocytosis. Lastly, clinicians should include thymoma in the differential diagnosis of T-cell lymphocytosis. If the cause of such lymphocytosis is not apparent, chest X-ray and CT scan of the thorax should be considered. ACKNOWLEDGMENTS
We are grateful to Susan E. Brown and Donna Cook for typing this manuscript. REFERENCES 1. Rosenow EC 111, Hurley BT: Disorders of the thymus. A review. Arch Intern Med 144:763-770, 1984.
2. Lewis JE, Wick MR, Scheithauer BW, Bermatz PE, Taylor W F Thymoma. A clinicopathologic review. Cancer 60:2727-2743, 1987. 3. Rogers HG, Manaligod JR, Blazer WH: Thymoma associated with pancytopenia and hypogammaglobulinemia. Report of a case and review of the literature. Am J Med 44:154-164, 1968. 4. Griffin JD, Aisenberg AC, Long JC: Lymphocytic thymoma associated with T-cell lymphocytosis. Am J Med 64:1075-1079, 1978. 5 . Pedraza MA: Thymoma immunological and ultrastructural characterization. Cancer 39:1455-1461, 1977. 6. Shachor Y,Radnay J, Bemheim J, Rozenszavn A, Bruderman I, Klajman A, Steiner ZP: Malignant thymoma with peripheral blood lymphocytosis. Cancer 61: 1222-1227, 1988. 7. Soler J, Estivill X, Ayats R, Brunet S, Pujol-Moix N: Chronic T-cell lymphocytosis associated with pure red cell aplasia, thymoma and hypogammaglobulinaemia. Br J Haematol61:582-584, 1985. 8. Strominger JL: Developmental biology of T-cell receptors. Science 244:943-950, 1989. 9. Foon KA, Todd RK 111: Immunologic classification of leukemia and lymphoma. Blood 68:l-31, 1986.
Malignant Thymoma Associated with Peripheral T-cell Lymphocytosis Donald C. Doll, MD, Rodney J. Landreneau, MD, and Alan F. List, MD Three cases of peripheral T-cell lyrnphocytosis associated with thymorna are described. Each patient had a malignant, predominantly lymphocytic thymoma with resolution of lyrnphocytosis upon treatment
of the epithelial neoplasm. These findings suggest that lyrnphocytosis complicating thymorna is a paraneoplastic phenomenon and is not part of the neoplastic process.
Key words: thymic neoplasm, leukocytosis
INTRODUCTION
Thymomas are epithelial neoplasms that may be associated with a variety of paraneoplastic syndromes [ 11. Hematologic abnormalities may be detected in 10% of patients [2] and include red cell aplasia, pancytopenia, and hypogammaglobulinemia [ 1,3]. Lymphocytosis associated with malignant thymoma has been reported rarely [4-71. We describe three cases of peripheral T-cell lymphocytosis associated with malignant thymoma with resolution of hematologic abnormalities upon treatment of the epithelial malignancy. These findings suggest that T-lymphocytosis is a paraneoplastic manifestation of thymoma and is not involved in the neoplastic process.
biopsy diagnosis. There was invasion into adjacent adipose tissue and the phrenic nerve margin was positive for tumor. Immunostaining of the surgical specimen revealed an antigenic profile consistent with thymic cortical lymphocytes (CD-4, CD-8, CD-2, CD-5, CD-7, and CD-9). Three weeks after resection the leukocyte count was 9.9 X lO’/liter with 32% lymphocytes with a normal distribution of lymphocyte subsets. Because of local tumor extension, external beam irradiation (5040 cGy) was administered to the AP and PA of the lung and right and left lateral lung fields. Three months after completion of treatment the absolute lymphocyte count remains in the normal range.
CASE 1
CASE 2
A 77-year-old male was admitted to the hospital for transurethral resection of the prostate. Physical exam revealed prostatic hypertrophy; there was no hepatosplenomegaly or lymphadenopathy. Chest X-ray and computed tomography (CT) of the chest disclosed an 8-cmdiameter mass in the anterior mediastinurn. Hemogram revealed a leukocyte count of 15.7 X 109/literwith 52% mature appearing lymphocytes; hemoglobin, 13.1 g/dl; and platelets, 978 X lO’/liter. Bone marrow aspirate and biopsy were normal with 14% lymphocytes. Immunophenotyping studies of the peripheral blood lymphocytes showed reactivity with pan-T cell antibodies (CD-5, 77%, CD-7, 79%; and CD-2, 83%). CT directed needle biopsy of the mass was nondiagnostic. Mediastinotomy biopsy was performed and histological exam showed a tumor composed predominantly of lymphocytes intermingled with epithelial cells consistent with lymphocytic thymoma. Surgical extirpation of the tumor was done and histologic studies confirmed the 0 1991 Wiley-Liss, Inc.
A 43-year-old male was hospitalized for evaluation of hoarseness and chest pain. Physical exam was normal. Chest X-ray and CT scan revealed an anterior mediastinal mass. Leukocyte count was 18.2 X lO’/liter with 62% small, mature appearing lym hocytes; hemoglobin, 14.7 g/dl; and platelets, 315 X 10! /liter. Immunophenotyping of peripheral lymphocytes disclosed a T-cell lineage (CD-5,73%; CD-7, 72%; and CD-2, 85%). Bone marrow aspiration and biopsy were normal with 19% lymphocytes. Needle biopsy of the tumor was inconclusive and a thoracotomy was performed. A mediastinal
From the Department of Medicine, Veterans Administration Hospital, Columbia, Missouri and Tucson, Arizona, and Department of Surgery, University of Missouri, Columbia, Missouri. Received October 9, 1990; accepted April 12, 1991. Address reprint requests to Dr. Donald C. Doll, Department of Medicine, Veterans Administration Hospital, Columbia, MO 65212.
Peripheral T-cell Lymphocytosis
497
TABLE I. Lymphocytosis Associated With Thymoma
Reference Case 1 Case 2 Case 3 Pedraza [5] Griffin et al. [4] Shachor et al. [6] Soler et al. [7]
Agelsex 77/M 43/M
56lM 69lM 64/F 371F 72lF
Histology thymoma
Absolute lymphocyte count/mm3
T-cell phenotype of peripheral blood
Lyrnphocytic Lymphocytic Lymphocytic Lymphocytic Lymphocytic Lymphocytic Lymphocytic
8164 11284 15028 10500 13156 24360 6200
Cortical thymocytes Cortical thymocytes Suppressor NAB NAa Helper Suppressor
aNA, not available.
mass was found to invade the heart and great vessels precluding surgical resection. Biopsy of the mass revealed lymphocytic thymoma. Five courses of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) were administered with a reduction in tumor size. A thoracotomy was performed and the remaining tumor was excised. Pathologic studies confirmed a thymoma of lymphocytic type with tumorfree margins. Immunophenotypically, the tumor lymphocytes expressed an antigenic pattern of cortical thymocytes (CD-5,60%; CD-7,69%; CD-2,95%). One month postoperatively the leukocyte count was 9.0 X 109/liter with 31% lymphocytes with normal cell marker studies. At 9 months follow-up the blood counts remain normal. CASE 3
A 55-year-old was hospitalized for treatment of pneumonia. A chest radiograph performed after resolution of the pulmonary infiltrates revealed an anterior mediastinal mass. Chest CT demonstrated a 5 X 7 cm thymic mass with extensive pleural deposits. At thoracotomy, diffuse nodular tumor deposits were noted involving the parietal and visceral pleura. Biopsy of the thymic and pleural masses revealed malignant thymoma of lymphocyte predominant type. The patient declined therapy at that time. Fourteen months later the patient returned with progressive chest pain and dyspnea. Chest CT demonstrated further enlargement of the mediastinal mass with confluence of the pleural nodules. The leukocyte count was 28.9 X 109/liter with 52% mature-appearing lymphocytes without azurophilic cytoplasmic granules. Lymphocyte typing disclosed a T-cell lymphocytosis with suppressor T-cell predominance (CD-3; 97%; CD-8, 52%;CD-4, 27%). A bone marrow aspirate and biopsy was unremarkable with 10% lymphocytes. The patient consented to treatment and six monthly courses of cisplatin and doxorubicin were administered with >75% reduction in tumor volume. One year after completion of
therapy the patient is symptom-free with a leukocyte count of 11.O X 109/literwith 32% lymphocytes. Pertinent data for patients with lymphocytosis and thymoma are depicted in Table I. DISCUSSION
These patients presented with a mediastinal mass and absolute lymphocytosis. Subsequent clinical and/or pathologic evaluation showed that each patient had a malignant thymoma, predominantly lymphocytic type, with local and/or pleural extension. Immunophenotypicanalysis of peripheral blood disclosed a T-cell lineage in all cases and in both cases of thymoma when phenotypic studies were performed. Of note, there was normalization of blood counts after completion of treatment of the underlying thymoma. Only four cases of thymoma associated with absolute lymphocytosishave been reported previously [4-7]. Like our cases, the patients harbored a predominantly lymphocytic thymoma, and peripheral T-cell lymphocytosis, and had resolution of the lymphocytosis following treatment. Three of the four cases were malignant [4-61. The pathogenesis of lymphocytosis associated with thymoma is unknown. Shachor et al. [6] suggested that lymphocytosis resulted from spillover of neoplastic helper T-cells derived from the thymic neoplasm. Concordance of the lymphocyte immunophenotypefrom the peripheral blood and thymic tumor in our cases supports the notion of peripheralization of tumor-derived lymphocytes. Our findings and those reported by Soler et al. [7], however, indicate that T-cell phenotype may vary and include either suppressor or helper T-lymphocytes, or an antigenic profile consistent with cortical thymocytes (i.e., CD4 and CD8 positive). Although we cannot exclude a clonal origin of the lymphocytosis, the absence of marrow involvement and resolution with locally directed therapy (e.g., Case 1) suggest that the cells remain under thymic regulation. T-cell receptor gene rearrangement studies would be helpful in future cases [8,9].
498
Doll et al.
In conclusion, absolute peripheral T-cell lymphocytosis may be associated with thymoma. To date all thymoma cases have been of the lymphocytic predominant type and six of the seven cases have been malignant. Additional studies are needed to elucidate the pathogenesis and cell of origin of the lymphocytosis. Lastly, clinicians should include thymoma in the differential diagnosis of T-cell lymphocytosis. If the cause of such lymphocytosis is not apparent, chest X-ray and CT scan of the thorax should be considered. ACKNOWLEDGMENTS
We are grateful to Susan E. Brown and Donna Cook for typing this manuscript. REFERENCES 1. Rosenow EC 111, Hurley BT: Disorders of the thymus. A review. Arch Intern Med 144:763-770, 1984.
2. Lewis JE, Wick MR, Scheithauer BW, Bermatz PE, Taylor W F Thymoma. A clinicopathologic review. Cancer 60:2727-2743, 1987. 3. Rogers HG, Manaligod JR, Blazer WH: Thymoma associated with pancytopenia and hypogammaglobulinemia. Report of a case and review of the literature. Am J Med 44:154-164, 1968. 4. Griffin JD, Aisenberg AC, Long JC: Lymphocytic thymoma associated with T-cell lymphocytosis. Am J Med 64:1075-1079, 1978. 5 . Pedraza MA: Thymoma immunological and ultrastructural characterization. Cancer 39:1455-1461, 1977. 6. Shachor Y,Radnay J, Bemheim J, Rozenszavn A, Bruderman I, Klajman A, Steiner ZP: Malignant thymoma with peripheral blood lymphocytosis. Cancer 61: 1222-1227, 1988. 7. Soler J, Estivill X, Ayats R, Brunet S, Pujol-Moix N: Chronic T-cell lymphocytosis associated with pure red cell aplasia, thymoma and hypogammaglobulinaemia. Br J Haematol61:582-584, 1985. 8. Strominger JL: Developmental biology of T-cell receptors. Science 244:943-950, 1989. 9. Foon KA, Todd RK 111: Immunologic classification of leukemia and lymphoma. Blood 68:l-31, 1986.
