Resph'atosT Medicine (1992) 86, 521-523
Recurrent venous thrombosis as the presenting sign of two primary lung carcinomas- 15 years apart C. PUTTERMAN*, B. TADMOR, L. SIMER AND Y. CARACO Department of Internal Medicine, Hadassah University Hospital, Ein-Kerem Jerusalem, Israel
Introduction The association between hypercoagulability and malignant disease was first recognized by Armand Trousseau in 1865. Since then, abnormalities of the coagulation system have been repeatedly demonstrated in patients with cancer. Venous thrombosis can be the presenting feature of neoplastic disease, particularly of the lung, preceding other signs of the malignancy by many months. We report a patient with Trousseau's syndrome, in which recurrent deep vein thrombosis was the presenting sign of two primary lung cancers, appearing 15 years apart.
Case Report A 73-year-old Russian immigrant woman presented with recurrent deep vein thrombosis. Sixteen years prior to the current admission, she suffered deep vein thrombosis in her left leg, and was successfully treated with intravenous heparin, followed by a short course of oral anti-coagulants (first admission). A year later, a mass in her right lower lobe was discovered on a routine chest X-ray film (second admission). The patient denied any personal history of smoking. A Iobectomy was performed, and histology showed localized bronchoalveolar carcinoma of the lung. No further treatment was deemed necessary, with no evidence of disease over the following 15 years. Two months prior to her admission, the patient presented to another hospital with pain and swelling of her left thigh (third admission). Both Doppler ultrasound and plethysmography strongly confirmed the clinical diagnosis of left deep vein thrombosis. Chest radiography was interpreted as normal, with only minimal scarring due to her previous thoracotomy. Received I August 1991 and accepted in revised form 27 December 1991. *To whom correspondence and reprint requests should be addressed Department of Internal Medicine A, Hadassah University Hospital, Kiryat Hadassah, P.O.B. 12000, Jerusalem 91120, Israel.
at:
0954-611 I/92/060521 + 03 $08.00/0
She was placed on intravenous heparin with good response, and was discharged on oral warfarin adjusted to bring the prothrombin time to 1-5 times the control value. Two days later, she presented with similar complaints in her right leg, and again was found to have deep vein thrombosis (fourth admission). After a longer course of intravenous heparin the thrombosis resolved, and the patient was discharged on oral warfarin which she continued for the next 2 months. Five days prior to admission, she developed fever up to 38°C with pain and swelling in her left thigh and calf, despite therapeutic prolongation of her prothrombin time on repeated testing. She presented to the Hadassah-Hebrew University Medical Center with clinical findings suggestive of deep vein thrombosis in her left leg (fifth admission). The left thigh and calf were significantly increased in diameter relative to the right side, with local erythema and tenderness on gentle deep palpation. Homans' sign was positive on the left. Doppler ultrasonography showed poor flow and compressibility of the left superficial and c~mmon femoral veins. Venography demonstrated only partial filling of the deep venous system, together with a rich collateral venous network. Multiple filling defects were seen in the left superficial and common femoral vein, continuing up to the common iliac vein. Warfarin was discontinued, and the patient received intravenous heparin for the remainder of her hospital course. Chest roentgenography (posterior-anterior view) revealed only slight volume loss in her right lower lung. No masses or pleural effusion could be seen. Minimal blunting of the right costo-phrenic angle was present. The lateral chest film added no further information. Routine laboratory evaluation was unremarkable, except for persistent thrombocytosis up to 485 x 10 9. Of the tumor markers measured because of the clinical suspicion of a paraneoplastic phenomenon, the CA-125 was markedly increased to 775U ml -t (normal < 50). Gynecological examination and pelvic ultrasound were normal. Computed tomography of © 1992 Bailli~re Tindall
522
C. Putterman et al.
the chest revealed an irregular mass, 3.0 cm in diameter in the right middle lobe, with local pleural thickening. Other lung regions were normal, and no mediastinal lymphadenopathy was seen. Computed tomography of the abdomen (with injection of contrast) also demonstrated the filling defect in the left common femoral vein extending up to the common iliac vein, as well as a filling defect in the right femoral vein. Transthoracic biopsy under guidance by computed tomography was performed, and pleomorphic adenocarcinoma of the lung, large cell type was found. A search for other possible sources of lung malignancy was negative. After a 2-week course of intravenous therapy, the patient was successfully weaned to subcutaneous heparin, given in two daily injections each of 15 000 units. Eventually, enlarging right posterior cervical lymph nodes were noted. The lymph nodes were nontender to touch, and hard in consistency. Cytologic examination of tissue obtained by fine-needle aspiration revealed neoplastic cells with morphology similar to the cells found in the lung biopsy. This finding precluded any possibility of effective definitive therapy for the second carcinoma. Nevertheless, the patient received a therapeutic course of irradiation to the right lung, in attempt to minimize any systemic procoagulant effect of the malignancy. On follow-up over the year since her last (fifth) admission, the patient is free from additional episodes of thrombosis, while continuing self-injections of subcutaneous heparin. Discussion
Bronchogenic carcinoma is a common and usually aggressive malignancy. Only a minority of patients presenting with this diagnosis are eligible for curative therapy. Long-term survival is possible, but is uncommon even in those patients undergoing curative therapy for localized disease. When compared to the frequency of a single lung carcinoma, multiple primary lung carcinoma is distinctly rare. The second primary lung carcinoma can occur simultaneously (synchronous), or with a considerable interval in between (metachronous), even after years of apparent cure (1-4). A well known manifestation of bronchogenic carcinoma is venous thromboembolism. The clinical picture can be suggestive: migratory and recurrent thrombosis, at times involving unusual sites, and particularly resistant to usual therapeutic measures. The incidence of thrombosis associated with lung cancer is steadily increasing, with the parallel increase in the prevalence of lung cancer in the population (5). Thromboembolic phenomena are thought to be
associated with a poorer prognosis than otherwise would be expected. In a large series of patients with lung cancer from the Mayo Clinic (6), the average survival from the event of thrombosis to death was less than 6 months. No relationship was found in this study between the histology of the tumor and the predisposition for thromboembolism. Several hypotheses have been advanced to explain the pathophysiology of cancer-associated coagulopathy (7,8). Antithrombin-III levels have been shown to be decreased in patients with cancer, perhaps due to malnutrition (9). Levels of Protein C, another naturally occurring anticoagulant, were found to be low in patients with cancer hypercoagulability. Specifically in patients with lung cancer, Maruyama et al. (10) recently reported the presence of thrombosis-inducing activity in the plasma of two patients with advanced lung cancer. There was evidence for chronic activation of the coagulation system in these patients, as indicated by increased levels of fibrinogen, fibrin-degradation-products, and peripheral platelet counts. Interestingly, the thrombosisinducing activity disappeared from the plasma of one patient following regression of the lung tumor after irradiation, with normalization of the levels of fibrinogen and fibrin-degradation-products. Maruyama et al. (11) have expanded their findings, and recently reported the-presence of thrombosisinducing activity in plasma of 13 of 42 patients with lung cancer, versus in only two of 31 healthy controls. Intravenous injection of plasma from these patients into mice or guinea-pigs resulted in massive pulmonary thromboses and death. The investigators speculate that the thrombosis-inducing activity may be due to a tissue factor like molecule, originating from the tumor cells, tumor-associated macrophages, or peripheral monocytes. Several other mechanisms have been suggested in some patients with cancer hypercoagulability. Shaukat and Hughes (12) described a patient with adenocarcinoma of the lung, associated with a high titre of anticardiolipin antibodies. The patient suffered from multiple recurring episodes of massive venous thrombosis eventually leading to his demise, despite therapy with immunosuppression and intensive anticoagulation with aspirin, warfarin and heparin. Shaukat and Hughes (12) raise the possibility that autoantibodies arising from an immune response directed primarily against tumor antigens may be responsible for anti-cardiolipin induced thrombotic m~nifestations in some patients with Trousseau's syndrome. Other authors have indicated a pathophysiological role in cancer coagulopathy also for an increase in the number and adhesiveness circulating
Recurrent venous thrombosis and lung cancer
platelets, disordered fibrinolysis, and the secretion of thromboplastin-like substances (8,13,14). It remains to be determined whether any specific mechanism is more characteristic of certain types of cancer. Nevertheless, the cautious clinician should screen for abnormalities of blood coagulation in all patients with cancer (15). Our patient was unique in several aspects. Firstly, the protracted survival period after the first primary lung cancer was manifested by thrombosis. Secondly, the notably long time lag before the occurrence of the second primary lung cancer. Thirdly, the cancerassociated coagulopathy appearing as the presenting sign of both the first and second primary malignancies of the lung, with an asymptomatic interval of 15 years between the two events. To our knowledge, this is the first such description of thrombosis also heralding the clinical expression of a second primary lung tumor. Episodes of recurrent, resistant, or unusually presenting thrombophlebitis should increase the clinician's index of suspicion for an underlying carcinoma, even after apparent cure of previous malignant disease.
References
1. Shields TW, Drake CT, Sherrick JC. Bilateral primary bronchogenic carcinoma. J Thorac Cardiovas Surg 1964; 48:401-417. 2. Martini N, Melamed MR. Multiple primary lung cancers. J Thorac Cardiovas Surg 1975;70: 606-612.
523
3. Sulkes A, Naparstek Y, Shalit M, Kopolovic J. Second primary lung carcinoma. JSurg Onco11980; 15: 375-380. 4. Chung TS. Multiple primary carcinoma of the lung. J Surg Onco11983; 24: 124-128. 5. Hyde L, Hyde CI. Clinical manifestations of lung cancer. Chest 1974;65: 299-306. 6. Byrd RB, Divertie MB, Spittell JA, Jr. Bronchogenic carcinoma and thromboembolic disease. J Am Med Assoc 1967;202:107-110. 7. Fengler SA, Berenberg Jl, Lee YTM. Disseminated coagulopathies and advanced malignancies. Am J Surg 1990; 56: 335-338. 8. Sack GH, Jr., Levin J, Bell WR. Trousseau's syndrome and other manifestations of chronic disseminated coagulopathy in patients with neoplasms: clinical, pathophysiologic, and therapeutic features. Medicine (Baltimore) 1977;56: 1-37. 9. Cohen JR, Tenenbaum N, Citron M. Greenfield filter as primary therapy for deep venous thrombosis and/or pulmonary embolism in patients with cancer. Surgery 1991; 109: 12-15. 10. Maruyama M, Yagawa K, Kinjo Met al. Thrombosisinducing activity found in plasma from two patients with advanced lung cancer. Oncology 1989;46:251-254. 11. Maruyama, Yagawa K, Hayashi S. et al. Presence of thrombosis-inducing activity in plasma from patients with lung cancer. An Rev Respir Dis 1989; 140: 778-781. 12. Shauket MN, HughesP. Recurrent thrombosis andanticardiolipin antibodies associated with adenocarcinoma of the lung. Postgrad Med J 1990;66:316-318. 13. Jose B, Mendoza EF, Tobin DA, Chu AM, Scott RM, Bland KI. Venous thrombosis and carcinoma of the lung: case report and literature review. J Surg Oncol 1982; 21: 54-56. 14. Harrison AC, Breslin ABX. Recurrent venous thrombosis (thrombophlebitis migrans) and carcinoma of the lung. MedJAust 1977; I: 927-929. 15. Rickles FR. Thrombosis and lung cancer. Am Rev Respir Dis 1989; 140: 573-575.
Recurrent venous thrombosis as the presenting sign of two primary lung carcinomas- 15 years apart C. PUTTERMAN*, B. TADMOR, L. SIMER AND Y. CARACO Department of Internal Medicine, Hadassah University Hospital, Ein-Kerem Jerusalem, Israel
Introduction The association between hypercoagulability and malignant disease was first recognized by Armand Trousseau in 1865. Since then, abnormalities of the coagulation system have been repeatedly demonstrated in patients with cancer. Venous thrombosis can be the presenting feature of neoplastic disease, particularly of the lung, preceding other signs of the malignancy by many months. We report a patient with Trousseau's syndrome, in which recurrent deep vein thrombosis was the presenting sign of two primary lung cancers, appearing 15 years apart.
Case Report A 73-year-old Russian immigrant woman presented with recurrent deep vein thrombosis. Sixteen years prior to the current admission, she suffered deep vein thrombosis in her left leg, and was successfully treated with intravenous heparin, followed by a short course of oral anti-coagulants (first admission). A year later, a mass in her right lower lobe was discovered on a routine chest X-ray film (second admission). The patient denied any personal history of smoking. A Iobectomy was performed, and histology showed localized bronchoalveolar carcinoma of the lung. No further treatment was deemed necessary, with no evidence of disease over the following 15 years. Two months prior to her admission, the patient presented to another hospital with pain and swelling of her left thigh (third admission). Both Doppler ultrasound and plethysmography strongly confirmed the clinical diagnosis of left deep vein thrombosis. Chest radiography was interpreted as normal, with only minimal scarring due to her previous thoracotomy. Received I August 1991 and accepted in revised form 27 December 1991. *To whom correspondence and reprint requests should be addressed Department of Internal Medicine A, Hadassah University Hospital, Kiryat Hadassah, P.O.B. 12000, Jerusalem 91120, Israel.
at:
0954-611 I/92/060521 + 03 $08.00/0
She was placed on intravenous heparin with good response, and was discharged on oral warfarin adjusted to bring the prothrombin time to 1-5 times the control value. Two days later, she presented with similar complaints in her right leg, and again was found to have deep vein thrombosis (fourth admission). After a longer course of intravenous heparin the thrombosis resolved, and the patient was discharged on oral warfarin which she continued for the next 2 months. Five days prior to admission, she developed fever up to 38°C with pain and swelling in her left thigh and calf, despite therapeutic prolongation of her prothrombin time on repeated testing. She presented to the Hadassah-Hebrew University Medical Center with clinical findings suggestive of deep vein thrombosis in her left leg (fifth admission). The left thigh and calf were significantly increased in diameter relative to the right side, with local erythema and tenderness on gentle deep palpation. Homans' sign was positive on the left. Doppler ultrasonography showed poor flow and compressibility of the left superficial and c~mmon femoral veins. Venography demonstrated only partial filling of the deep venous system, together with a rich collateral venous network. Multiple filling defects were seen in the left superficial and common femoral vein, continuing up to the common iliac vein. Warfarin was discontinued, and the patient received intravenous heparin for the remainder of her hospital course. Chest roentgenography (posterior-anterior view) revealed only slight volume loss in her right lower lung. No masses or pleural effusion could be seen. Minimal blunting of the right costo-phrenic angle was present. The lateral chest film added no further information. Routine laboratory evaluation was unremarkable, except for persistent thrombocytosis up to 485 x 10 9. Of the tumor markers measured because of the clinical suspicion of a paraneoplastic phenomenon, the CA-125 was markedly increased to 775U ml -t (normal < 50). Gynecological examination and pelvic ultrasound were normal. Computed tomography of © 1992 Bailli~re Tindall
522
C. Putterman et al.
the chest revealed an irregular mass, 3.0 cm in diameter in the right middle lobe, with local pleural thickening. Other lung regions were normal, and no mediastinal lymphadenopathy was seen. Computed tomography of the abdomen (with injection of contrast) also demonstrated the filling defect in the left common femoral vein extending up to the common iliac vein, as well as a filling defect in the right femoral vein. Transthoracic biopsy under guidance by computed tomography was performed, and pleomorphic adenocarcinoma of the lung, large cell type was found. A search for other possible sources of lung malignancy was negative. After a 2-week course of intravenous therapy, the patient was successfully weaned to subcutaneous heparin, given in two daily injections each of 15 000 units. Eventually, enlarging right posterior cervical lymph nodes were noted. The lymph nodes were nontender to touch, and hard in consistency. Cytologic examination of tissue obtained by fine-needle aspiration revealed neoplastic cells with morphology similar to the cells found in the lung biopsy. This finding precluded any possibility of effective definitive therapy for the second carcinoma. Nevertheless, the patient received a therapeutic course of irradiation to the right lung, in attempt to minimize any systemic procoagulant effect of the malignancy. On follow-up over the year since her last (fifth) admission, the patient is free from additional episodes of thrombosis, while continuing self-injections of subcutaneous heparin. Discussion
Bronchogenic carcinoma is a common and usually aggressive malignancy. Only a minority of patients presenting with this diagnosis are eligible for curative therapy. Long-term survival is possible, but is uncommon even in those patients undergoing curative therapy for localized disease. When compared to the frequency of a single lung carcinoma, multiple primary lung carcinoma is distinctly rare. The second primary lung carcinoma can occur simultaneously (synchronous), or with a considerable interval in between (metachronous), even after years of apparent cure (1-4). A well known manifestation of bronchogenic carcinoma is venous thromboembolism. The clinical picture can be suggestive: migratory and recurrent thrombosis, at times involving unusual sites, and particularly resistant to usual therapeutic measures. The incidence of thrombosis associated with lung cancer is steadily increasing, with the parallel increase in the prevalence of lung cancer in the population (5). Thromboembolic phenomena are thought to be
associated with a poorer prognosis than otherwise would be expected. In a large series of patients with lung cancer from the Mayo Clinic (6), the average survival from the event of thrombosis to death was less than 6 months. No relationship was found in this study between the histology of the tumor and the predisposition for thromboembolism. Several hypotheses have been advanced to explain the pathophysiology of cancer-associated coagulopathy (7,8). Antithrombin-III levels have been shown to be decreased in patients with cancer, perhaps due to malnutrition (9). Levels of Protein C, another naturally occurring anticoagulant, were found to be low in patients with cancer hypercoagulability. Specifically in patients with lung cancer, Maruyama et al. (10) recently reported the presence of thrombosis-inducing activity in the plasma of two patients with advanced lung cancer. There was evidence for chronic activation of the coagulation system in these patients, as indicated by increased levels of fibrinogen, fibrin-degradation-products, and peripheral platelet counts. Interestingly, the thrombosisinducing activity disappeared from the plasma of one patient following regression of the lung tumor after irradiation, with normalization of the levels of fibrinogen and fibrin-degradation-products. Maruyama et al. (11) have expanded their findings, and recently reported the-presence of thrombosisinducing activity in plasma of 13 of 42 patients with lung cancer, versus in only two of 31 healthy controls. Intravenous injection of plasma from these patients into mice or guinea-pigs resulted in massive pulmonary thromboses and death. The investigators speculate that the thrombosis-inducing activity may be due to a tissue factor like molecule, originating from the tumor cells, tumor-associated macrophages, or peripheral monocytes. Several other mechanisms have been suggested in some patients with cancer hypercoagulability. Shaukat and Hughes (12) described a patient with adenocarcinoma of the lung, associated with a high titre of anticardiolipin antibodies. The patient suffered from multiple recurring episodes of massive venous thrombosis eventually leading to his demise, despite therapy with immunosuppression and intensive anticoagulation with aspirin, warfarin and heparin. Shaukat and Hughes (12) raise the possibility that autoantibodies arising from an immune response directed primarily against tumor antigens may be responsible for anti-cardiolipin induced thrombotic m~nifestations in some patients with Trousseau's syndrome. Other authors have indicated a pathophysiological role in cancer coagulopathy also for an increase in the number and adhesiveness circulating
Recurrent venous thrombosis and lung cancer
platelets, disordered fibrinolysis, and the secretion of thromboplastin-like substances (8,13,14). It remains to be determined whether any specific mechanism is more characteristic of certain types of cancer. Nevertheless, the cautious clinician should screen for abnormalities of blood coagulation in all patients with cancer (15). Our patient was unique in several aspects. Firstly, the protracted survival period after the first primary lung cancer was manifested by thrombosis. Secondly, the notably long time lag before the occurrence of the second primary lung cancer. Thirdly, the cancerassociated coagulopathy appearing as the presenting sign of both the first and second primary malignancies of the lung, with an asymptomatic interval of 15 years between the two events. To our knowledge, this is the first such description of thrombosis also heralding the clinical expression of a second primary lung tumor. Episodes of recurrent, resistant, or unusually presenting thrombophlebitis should increase the clinician's index of suspicion for an underlying carcinoma, even after apparent cure of previous malignant disease.
References
1. Shields TW, Drake CT, Sherrick JC. Bilateral primary bronchogenic carcinoma. J Thorac Cardiovas Surg 1964; 48:401-417. 2. Martini N, Melamed MR. Multiple primary lung cancers. J Thorac Cardiovas Surg 1975;70: 606-612.
523
3. Sulkes A, Naparstek Y, Shalit M, Kopolovic J. Second primary lung carcinoma. JSurg Onco11980; 15: 375-380. 4. Chung TS. Multiple primary carcinoma of the lung. J Surg Onco11983; 24: 124-128. 5. Hyde L, Hyde CI. Clinical manifestations of lung cancer. Chest 1974;65: 299-306. 6. Byrd RB, Divertie MB, Spittell JA, Jr. Bronchogenic carcinoma and thromboembolic disease. J Am Med Assoc 1967;202:107-110. 7. Fengler SA, Berenberg Jl, Lee YTM. Disseminated coagulopathies and advanced malignancies. Am J Surg 1990; 56: 335-338. 8. Sack GH, Jr., Levin J, Bell WR. Trousseau's syndrome and other manifestations of chronic disseminated coagulopathy in patients with neoplasms: clinical, pathophysiologic, and therapeutic features. Medicine (Baltimore) 1977;56: 1-37. 9. Cohen JR, Tenenbaum N, Citron M. Greenfield filter as primary therapy for deep venous thrombosis and/or pulmonary embolism in patients with cancer. Surgery 1991; 109: 12-15. 10. Maruyama M, Yagawa K, Kinjo Met al. Thrombosisinducing activity found in plasma from two patients with advanced lung cancer. Oncology 1989;46:251-254. 11. Maruyama, Yagawa K, Hayashi S. et al. Presence of thrombosis-inducing activity in plasma from patients with lung cancer. An Rev Respir Dis 1989; 140: 778-781. 12. Shauket MN, HughesP. Recurrent thrombosis andanticardiolipin antibodies associated with adenocarcinoma of the lung. Postgrad Med J 1990;66:316-318. 13. Jose B, Mendoza EF, Tobin DA, Chu AM, Scott RM, Bland KI. Venous thrombosis and carcinoma of the lung: case report and literature review. J Surg Oncol 1982; 21: 54-56. 14. Harrison AC, Breslin ABX. Recurrent venous thrombosis (thrombophlebitis migrans) and carcinoma of the lung. MedJAust 1977; I: 927-929. 15. Rickles FR. Thrombosis and lung cancer. Am Rev Respir Dis 1989; 140: 573-575.
