J Gastrointest Canc (2015) 46:182–184 DOI 10.1007/s12029-015-9697-0
CASE REPORT
Pulmonary Embolism and Stroke as the Initial Manifestation of Advanced Metastatic Pancreatic Adenocarcinoma Sudeep Dhoj Thapa & Hiba Hadid & Mohammad Usman
Published online: 6 March 2015 # Springer Science+Business Media New York 2015
Abbreviations LMWH Low molecular weight heparin DVT Deep venous thrombosis PE Pulmonary embolism TF Tissue factor
Introduction Pancreatic cancer is a common gastrointestinal malignancy with poor prognosis and is the fourth leading cause of cancer-related death in the USA [1]. Pancreatic cancer is caused by successive accumulation of mutations which causes the change of pancreatic tissue from premalignant to malignant, finally leading to invasion and metastasis [2]. It is associated with increased risk of thromboembolism as marked by the classical Trousseau’s sign which manifests as migratory thrombophlebitis. This is a rare case report of simultaneous stroke and pulmonary embolism as the initial presentation of pancreatic adenocarcinoma.
Case Report A 58-year-old African American male presented with complaints of transient speech and gait abnormality for 1 day. Informed consent was not obtained because patient had died by the time this article was written and patient's remaining family members could not be contacted. However, all individual patient identifiers have been masked without altering clinical or scientific meaning. S. D. Thapa (*) : H. Hadid : M. Usman Henry Ford Hospital, 2799 West Grand Blvd., Detroit, MI, USA e-mail: [email protected] S. D. Thapa e-mail: [email protected]
He had history of smoking, hypertension, and coronary artery disease. He also had history of diabetes mellitus type 2, which was diagnosed 1 year prior and was not well controlled. He had been treated with multiple medications including highdose insulin but remained persistently hyperglycemic. On presentation, he complained of Bslurring of speech^ and inability to Bthink of the right words.^ He also complained of swelling and tenderness in the right calf for 3 days. The calf swelling was associated with mild chest discomfort for 1 day which resolved spontaneously. He denied fever, headache, palpitations, and weakness in his limbs. On presenting to the hospital, he had mild confusion. On physical examination, he was noted to have expressive aphasia and flattening of the left nasolabial fold. He also had left calf tenderness, warmth, and swelling. On laboratory investigations, indeterminate range elevation of troponin I at 0.12mcg/L was noted. However, he did not have angina, and there were no new electrocardiogram changes. Computed tomography (CT) scan of the head did not show any acute abnormalities. However, because of the strong suspicion for possible acute cerebrovascular event, diffusion-weighted magnetic resonance imaging (MRI) of the brain was done which showed multiple areas of acute infarction involving the left frontal lobe, occipital lobe, and cerebellum (Fig. 1). CT scan of the chest showed multiple small bilateral emboli. He also had left common femoral deep venous thrombosis. CT scan of the abdomen showed a hypodense mass within the body-tail junction of the pancreas measuring 4.8×3 cm, and multiple masses were noted throughout the liver (Fig. 2). The liver masses were consistent with metastatic lesions. A 2-D echocardiogram was done later during the hospital course which did not show shunts, intracardiac thrombus, or vegetation. He also did not have any history of patent foramen ovale, atrial septal defect, or ventricular septal defect. Therefore, there was no communication between the venous and arterial circulation and had probably developed venous and arterial thromboembolism separately.
J Gastrointest Canc (2015) 46:182–184
Fig. 1 Magnetic resonance imaging of the brain showing multifocal ischemic stroke in the occipital region
A liver biopsy of the metastatic mass was done during the hospital stay which confirmed pancreatic adenocarcinoma. He was started on anticoagulation with low molecular weight heparin (LMWH). Despite anticoagulation, he suffered another stroke within a month. He died within 3 months of diagnosis.
Discussion Our report is a rare case of pancreatic cancer presenting with pulmonary embolism and stroke. A review of literature revealed only one other case of combined venous and arterial thromboembolism as initial presentation of pancreatic cancer in a patient with fatal metastatic disease [3]. The presenting symptoms of pancreatic cancer are generally nonspecific and depend on tumor location within the pancreas and also on the stage of disease. The majority of tumors
Fig. 2 Computed tomography scan of the abdomen showing pancreatic mass in the body-tail junction and multiple liver metastases
183
develops in the head of the pancreas and present with dull upper abdominal pain and obstructive jaundice; more rarely, it can present as gastrointestinal bleeding, deep or superficial venous thrombosis, gastrointestinal obstruction, or increased abdominal girth [2]. Physical examination may reveal jaundice, temporal wasting, peripheral lymphadenopathy, hepatomegaly, and ascites, and results of routine blood tests are generally nonspecific and may include mild abnormalities in liver function tests, hyperglycemia, and anemia [2]. Notably, our patient’s tumor was located in the body-tail junction of the pancreas and not in the head of the pancreas; therefore, he did not present with typical signs and symptoms and did not have abdominal pain or obstructive jaundice at presentation. Since Armand Trousseau’s first description of the relationship between migratory thrombophlebitis and malignancy in 1865, thromboembolism has been observed in many types of cancers. Malignancy in general and pancreatic adenocarcinoma in particular is associated with intravascular thrombosis. Deep venous thrombosis is a well-known manifestation of pancreatic cancer and occurs in 17–57 % of patients [4]. There have been reports of arterial thromboembolism, albeit uncommon compared to its venous counterpart. Our patient had cerebral infarction with small embolic infarctions affecting multiple vascular territories, which is consistent with cancerrelated stroke [5]. Furthermore, he had recurrent embolic stroke within a month after suffering from the initial stroke which illustrates the high risk of arterial thromboembolism in pancreatic cancer patients. Pancreatic cancer is associated with increase in three procoagulants—tissue factor (TF), thrombin, and fibrinogen [6]. TF overexpression is associated with cancer-associated thrombosis and tumor processes including angiogenesis [7]. TF activity is also a marker of tumor grade [8]. Hypercoagulability in pancreatic cancer is also known to promote angiogenesis, inflammation, and metastasis [6]. Therefore, thromboembolism could signal the presence of high-grade metastatic pancreatic cancer. Thromboembolism in pancreatic cancer is an ominous sign and portends a worse prognosis [9]. Treatment of cancer-related thrombosis is also challenging as these patients are at increased risk of recurrent thromboembolism. In recent years, low molecular weight heparin (LMWH) has become the drug of choice in cancer-related thromboembolism as it exerts both anticoagulant and antiangiogenic effects. A large trial done by Lee and colleagues established that low molecular weight heparin is more effective than oral anticoagulants in preventing recurrent thromboembolism in patients with cancer without increasing the risk of bleeding [10]. Furthermore, a recent meta-analysis showed benefit of LMWH in preventing DVT and PE in cancer patients, with the greatest benefit accrued by pancreatic cancer patients [11]. However, there is no data to guide management in pancreatic cancer patients with arterial thromboembolism.
184
Notably, our patient had new-onset uncontrolled diabetes mellitus type 2 which was diagnosed 1 year prior to the index presentation. It is known that older patients with new-onset diabetes have about an eight times higher risk of having pancreatic cancer than the general population; however, the use of new-onset diabetes as a screening tool for pancreatic cancer has not been feasible so far [12]. Patients with pancreatic cancer-induced diabetes are generally diagnosed with diabetes within 2 years prior to being diagnosed with cancer, and interestingly, resection of the pancreatic cancer can ameliorate diabetes in these patients [12]. Diabetes in these patients is unlikely to be secondary to destruction of the pancreas by cancer because insulin and C-peptide levels are generally high in patients with pancreatic cancer-induced diabetes [12]. The pathogenesis of pancreatic cancer-induced diabetes is not completely understood. It is also possible that new-onset diabetes could have contributed to the development of venous and arterial thromboembolism in our patient. Additionally, our patient had multiple other comorbidities including male gender, smoking, coronary artery disease, and hypertension which could have contributed to the development of thromboembolism. However, the distribution and recurrence of ischemic stroke and the catastrophic presentation are consistent with pancreatic cancer-induced thromboembolism.
Conclusion We present a unique case of fatal metastatic pancreatic adenocarcinoma presenting with new-onset diabetes mellitus type 2 and combined venous and arterial thromboembolism. Although the presenting features of pancreatic cancer are often nonspecific with most patients presenting with abdominal pain and obstructive jaundice, physicians should be aware of this rare presentation.
Conflict of Interest There are no conflicts of interest.
J Gastrointest Canc (2015) 46:182–184
References 1. Ryan DP, Hong TS, Bardeesy N. Pancreatic adenocarcinoma. N Engl J Med. 2014;371:1039–49. Available from: http://www.ncbi.nlm.nih. gov/pubmed/25207767. 2. Hidalgo M. Pancreatic cancer. N Engl J Med. 2010;362:1605–17. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20427809. 3. Majumder S, Thom T, Dasanu CA. Catastrophic arteriovenous thromboembolism as initial manifestation of pancreatic cancer. JOP. 2012;13:231–4. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/22406609. 4. Khorana AA, Fine RL. Pancreatic cancer and thromboembolic disease. Lancet Oncol. 2004;5:655–63. Available from: http://www. ncbi.nlm.nih.gov/pubmed/15522652. 5. Schwarzbach CJ, Schaefer A, Ebert A, Held V, Bolognese M, Kablau M, et al. Stroke and cancer: the importance of cancer-associated hypercoagulation as a possible stroke etiology. Stroke. 2012;43: 3029–34. Available from: http://stroke.ahajournals.org/content/43/ 11/3029.long. 6. Nakchbandi IA, Löhr J-M. Coagulation, anticoagulation and pancreatic carcinoma. Nat Clin Pract Gastroenterol Hepatol. 2008;5:445– 55. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 18594494. 7. Kasthuri RS, Taubman MB, Mackman N. Role of tissue factor in cancer. J Clin Oncol. 2009;27:4834–8. Available from: http://www. pubmedcentral.nih.gov/articlerender.fcgi?artid=2764391&tool= pmcentrez&rendertype=abstract. 8. Kakkar AK, Lemoine NR, Scully MF, Tebbutt S, Williamson RC. Tissue factor expression correlates with histological grade in human pancreatic cancer. Br J Surg. 1995;82:1101–4. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/7648165. 9. Mandalà M, Reni M, Cascinu S, Barni S, Floriani I, Cereda S, et al. Venous thromboembolism predicts poor prognosis in irresectable pancreatic cancer patients. Ann Oncol. 2007;18:1660–5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17660490. 10. Lee AYY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349:146–53. Available from: http://www. ncbi.nlm.nih.gov/pubmed/12853587. 11. Ben-Aharon I, Stemmer SM, Leibovici L, Shpilberg O, Sulkes A, Gafter-Gvili A. Low molecular weight heparin (LMWH) for primary thrombo-prophylaxis in patients with solid malignancies—systematic review and meta-analysis. Acta Oncol. 2014;53:1230–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25162954. 12. Pannala R, Basu A, Petersen GM, Chari ST. New-onset diabetes: a potential clue to the early diagnosis of pancreatic cancer. Lancet Oncol. 2009;10:88–95. Available from: http:// w w w. p u b m e d c e n t ra l . n i h . g o v / a r t i c l e re n d e r. f c g i ? a r t i d = 2795483&tool=pmcentrez&rendertype=abstract.
CASE REPORT
Pulmonary Embolism and Stroke as the Initial Manifestation of Advanced Metastatic Pancreatic Adenocarcinoma Sudeep Dhoj Thapa & Hiba Hadid & Mohammad Usman
Published online: 6 March 2015 # Springer Science+Business Media New York 2015
Abbreviations LMWH Low molecular weight heparin DVT Deep venous thrombosis PE Pulmonary embolism TF Tissue factor
Introduction Pancreatic cancer is a common gastrointestinal malignancy with poor prognosis and is the fourth leading cause of cancer-related death in the USA [1]. Pancreatic cancer is caused by successive accumulation of mutations which causes the change of pancreatic tissue from premalignant to malignant, finally leading to invasion and metastasis [2]. It is associated with increased risk of thromboembolism as marked by the classical Trousseau’s sign which manifests as migratory thrombophlebitis. This is a rare case report of simultaneous stroke and pulmonary embolism as the initial presentation of pancreatic adenocarcinoma.
Case Report A 58-year-old African American male presented with complaints of transient speech and gait abnormality for 1 day. Informed consent was not obtained because patient had died by the time this article was written and patient's remaining family members could not be contacted. However, all individual patient identifiers have been masked without altering clinical or scientific meaning. S. D. Thapa (*) : H. Hadid : M. Usman Henry Ford Hospital, 2799 West Grand Blvd., Detroit, MI, USA e-mail: [email protected] S. D. Thapa e-mail: [email protected]
He had history of smoking, hypertension, and coronary artery disease. He also had history of diabetes mellitus type 2, which was diagnosed 1 year prior and was not well controlled. He had been treated with multiple medications including highdose insulin but remained persistently hyperglycemic. On presentation, he complained of Bslurring of speech^ and inability to Bthink of the right words.^ He also complained of swelling and tenderness in the right calf for 3 days. The calf swelling was associated with mild chest discomfort for 1 day which resolved spontaneously. He denied fever, headache, palpitations, and weakness in his limbs. On presenting to the hospital, he had mild confusion. On physical examination, he was noted to have expressive aphasia and flattening of the left nasolabial fold. He also had left calf tenderness, warmth, and swelling. On laboratory investigations, indeterminate range elevation of troponin I at 0.12mcg/L was noted. However, he did not have angina, and there were no new electrocardiogram changes. Computed tomography (CT) scan of the head did not show any acute abnormalities. However, because of the strong suspicion for possible acute cerebrovascular event, diffusion-weighted magnetic resonance imaging (MRI) of the brain was done which showed multiple areas of acute infarction involving the left frontal lobe, occipital lobe, and cerebellum (Fig. 1). CT scan of the chest showed multiple small bilateral emboli. He also had left common femoral deep venous thrombosis. CT scan of the abdomen showed a hypodense mass within the body-tail junction of the pancreas measuring 4.8×3 cm, and multiple masses were noted throughout the liver (Fig. 2). The liver masses were consistent with metastatic lesions. A 2-D echocardiogram was done later during the hospital course which did not show shunts, intracardiac thrombus, or vegetation. He also did not have any history of patent foramen ovale, atrial septal defect, or ventricular septal defect. Therefore, there was no communication between the venous and arterial circulation and had probably developed venous and arterial thromboembolism separately.
J Gastrointest Canc (2015) 46:182–184
Fig. 1 Magnetic resonance imaging of the brain showing multifocal ischemic stroke in the occipital region
A liver biopsy of the metastatic mass was done during the hospital stay which confirmed pancreatic adenocarcinoma. He was started on anticoagulation with low molecular weight heparin (LMWH). Despite anticoagulation, he suffered another stroke within a month. He died within 3 months of diagnosis.
Discussion Our report is a rare case of pancreatic cancer presenting with pulmonary embolism and stroke. A review of literature revealed only one other case of combined venous and arterial thromboembolism as initial presentation of pancreatic cancer in a patient with fatal metastatic disease [3]. The presenting symptoms of pancreatic cancer are generally nonspecific and depend on tumor location within the pancreas and also on the stage of disease. The majority of tumors
Fig. 2 Computed tomography scan of the abdomen showing pancreatic mass in the body-tail junction and multiple liver metastases
183
develops in the head of the pancreas and present with dull upper abdominal pain and obstructive jaundice; more rarely, it can present as gastrointestinal bleeding, deep or superficial venous thrombosis, gastrointestinal obstruction, or increased abdominal girth [2]. Physical examination may reveal jaundice, temporal wasting, peripheral lymphadenopathy, hepatomegaly, and ascites, and results of routine blood tests are generally nonspecific and may include mild abnormalities in liver function tests, hyperglycemia, and anemia [2]. Notably, our patient’s tumor was located in the body-tail junction of the pancreas and not in the head of the pancreas; therefore, he did not present with typical signs and symptoms and did not have abdominal pain or obstructive jaundice at presentation. Since Armand Trousseau’s first description of the relationship between migratory thrombophlebitis and malignancy in 1865, thromboembolism has been observed in many types of cancers. Malignancy in general and pancreatic adenocarcinoma in particular is associated with intravascular thrombosis. Deep venous thrombosis is a well-known manifestation of pancreatic cancer and occurs in 17–57 % of patients [4]. There have been reports of arterial thromboembolism, albeit uncommon compared to its venous counterpart. Our patient had cerebral infarction with small embolic infarctions affecting multiple vascular territories, which is consistent with cancerrelated stroke [5]. Furthermore, he had recurrent embolic stroke within a month after suffering from the initial stroke which illustrates the high risk of arterial thromboembolism in pancreatic cancer patients. Pancreatic cancer is associated with increase in three procoagulants—tissue factor (TF), thrombin, and fibrinogen [6]. TF overexpression is associated with cancer-associated thrombosis and tumor processes including angiogenesis [7]. TF activity is also a marker of tumor grade [8]. Hypercoagulability in pancreatic cancer is also known to promote angiogenesis, inflammation, and metastasis [6]. Therefore, thromboembolism could signal the presence of high-grade metastatic pancreatic cancer. Thromboembolism in pancreatic cancer is an ominous sign and portends a worse prognosis [9]. Treatment of cancer-related thrombosis is also challenging as these patients are at increased risk of recurrent thromboembolism. In recent years, low molecular weight heparin (LMWH) has become the drug of choice in cancer-related thromboembolism as it exerts both anticoagulant and antiangiogenic effects. A large trial done by Lee and colleagues established that low molecular weight heparin is more effective than oral anticoagulants in preventing recurrent thromboembolism in patients with cancer without increasing the risk of bleeding [10]. Furthermore, a recent meta-analysis showed benefit of LMWH in preventing DVT and PE in cancer patients, with the greatest benefit accrued by pancreatic cancer patients [11]. However, there is no data to guide management in pancreatic cancer patients with arterial thromboembolism.
184
Notably, our patient had new-onset uncontrolled diabetes mellitus type 2 which was diagnosed 1 year prior to the index presentation. It is known that older patients with new-onset diabetes have about an eight times higher risk of having pancreatic cancer than the general population; however, the use of new-onset diabetes as a screening tool for pancreatic cancer has not been feasible so far [12]. Patients with pancreatic cancer-induced diabetes are generally diagnosed with diabetes within 2 years prior to being diagnosed with cancer, and interestingly, resection of the pancreatic cancer can ameliorate diabetes in these patients [12]. Diabetes in these patients is unlikely to be secondary to destruction of the pancreas by cancer because insulin and C-peptide levels are generally high in patients with pancreatic cancer-induced diabetes [12]. The pathogenesis of pancreatic cancer-induced diabetes is not completely understood. It is also possible that new-onset diabetes could have contributed to the development of venous and arterial thromboembolism in our patient. Additionally, our patient had multiple other comorbidities including male gender, smoking, coronary artery disease, and hypertension which could have contributed to the development of thromboembolism. However, the distribution and recurrence of ischemic stroke and the catastrophic presentation are consistent with pancreatic cancer-induced thromboembolism.
Conclusion We present a unique case of fatal metastatic pancreatic adenocarcinoma presenting with new-onset diabetes mellitus type 2 and combined venous and arterial thromboembolism. Although the presenting features of pancreatic cancer are often nonspecific with most patients presenting with abdominal pain and obstructive jaundice, physicians should be aware of this rare presentation.
Conflict of Interest There are no conflicts of interest.
J Gastrointest Canc (2015) 46:182–184
References 1. Ryan DP, Hong TS, Bardeesy N. Pancreatic adenocarcinoma. N Engl J Med. 2014;371:1039–49. Available from: http://www.ncbi.nlm.nih. gov/pubmed/25207767. 2. Hidalgo M. Pancreatic cancer. N Engl J Med. 2010;362:1605–17. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20427809. 3. Majumder S, Thom T, Dasanu CA. Catastrophic arteriovenous thromboembolism as initial manifestation of pancreatic cancer. JOP. 2012;13:231–4. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/22406609. 4. Khorana AA, Fine RL. Pancreatic cancer and thromboembolic disease. Lancet Oncol. 2004;5:655–63. Available from: http://www. ncbi.nlm.nih.gov/pubmed/15522652. 5. Schwarzbach CJ, Schaefer A, Ebert A, Held V, Bolognese M, Kablau M, et al. Stroke and cancer: the importance of cancer-associated hypercoagulation as a possible stroke etiology. Stroke. 2012;43: 3029–34. Available from: http://stroke.ahajournals.org/content/43/ 11/3029.long. 6. Nakchbandi IA, Löhr J-M. Coagulation, anticoagulation and pancreatic carcinoma. Nat Clin Pract Gastroenterol Hepatol. 2008;5:445– 55. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 18594494. 7. Kasthuri RS, Taubman MB, Mackman N. Role of tissue factor in cancer. J Clin Oncol. 2009;27:4834–8. Available from: http://www. pubmedcentral.nih.gov/articlerender.fcgi?artid=2764391&tool= pmcentrez&rendertype=abstract. 8. Kakkar AK, Lemoine NR, Scully MF, Tebbutt S, Williamson RC. Tissue factor expression correlates with histological grade in human pancreatic cancer. Br J Surg. 1995;82:1101–4. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/7648165. 9. Mandalà M, Reni M, Cascinu S, Barni S, Floriani I, Cereda S, et al. Venous thromboembolism predicts poor prognosis in irresectable pancreatic cancer patients. Ann Oncol. 2007;18:1660–5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17660490. 10. Lee AYY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349:146–53. Available from: http://www. ncbi.nlm.nih.gov/pubmed/12853587. 11. Ben-Aharon I, Stemmer SM, Leibovici L, Shpilberg O, Sulkes A, Gafter-Gvili A. Low molecular weight heparin (LMWH) for primary thrombo-prophylaxis in patients with solid malignancies—systematic review and meta-analysis. Acta Oncol. 2014;53:1230–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25162954. 12. Pannala R, Basu A, Petersen GM, Chari ST. New-onset diabetes: a potential clue to the early diagnosis of pancreatic cancer. Lancet Oncol. 2009;10:88–95. Available from: http:// w w w. p u b m e d c e n t ra l . n i h . g o v / a r t i c l e re n d e r. f c g i ? a r t i d = 2795483&tool=pmcentrez&rendertype=abstract.
