Novel Insights from Clinical Practice Gynecol Obstet Invest DOI: 10.1159/000487046 Received: July 18, 2017 Accepted after revision: January 19, 2018 Published online: June 8, 2018 Pancreatic Cancer in Pregnancy Presenting with Thromboembolic Events: Case Report and Review of the Literature Brian W. Wakefield a Crystal M.C. Masterson b Manuel T. Borges c K. Joseph Hurt a a Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora, CO, USA; b University of Colorado College of Nursing, Aurora, CO, USA; c Department of Neuroradiology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, USA Established Facts • Malignancy and pregnancy are both hypercoagulable states with increased risk for thromboembolic complications. • There are no established criteria for advanced imaging and workup of paraneoplastic hypercoagulability and occult malignancy in pregnancy. Novel Insights • Occult malignancy should be evaluated early in pregnant patients presenting with unexplained or recurrent stroke, Budd-Chiari Syndrome, or arterial thrombosis. • To facilitate earlier diagnosis, an evidence-based algorithm for the diagnosis of occult malignancy following thromboembolic events can be adapted to the pregnant-patient population. Abstract Stroke and hepatic vein thrombosis are highly associated with neoplasia but are extremely rare events in young, pregnant women. Rare and recurrent thrombotic events in pregnancy increase the suspicion for occult malignancy. We describe the case of a healthy 31-year-old G2P1 who presented © 2018 S. Karger AG, Basel E-Mail karger@karger.com www.karger.com/goi with visual changes and dysarthria during pregnancy. Imaging showed cerebral infarcts. Her thrombophilia evaluation was negative. During delivery, she was diagnosed with fulminant Budd-Chiari Syndrome. Hepatic ultrasound suggested malignancy or metastasis, and postpartum CT scan and biopsy confirmed the diagnosis of Stage IV pancreatic cancer. Although rare in pregnancy, a new diagnosis of malignancy should be considered in patients with recurrent unexplained hypercoagulable complications. We propose an evidencebased algorithm for evaluation of occult malignancy in pregnancy based upon this case and review of the literature. © 2018 S. Karger AG, Basel K. Joseph Hurt 12700 East 19th Avenue, Mailstop 8613 Research Complex-2, P15-3005 Aurora, CO 80045 (USA) E-Mail K.Joseph.Hurt @ UCDenver.edu Downloaded by: Leiden University Medisch Centrum 132.229.13.63 - 6/11/2018 1:13:55 PM Keywords Pancreatic neoplasm · Budd-Chiari syndrome · Cerebrovascular stroke · Thromboembolism · Pregnancy complications Pregnancy is a hypercoagulable state with an increased absolute risk of venous thromboembolism (VTE) that is 7–10% higher than age-matched controls [1]. Estrogendependent increases in hepatic clotting factors, altered hemodynamics, and venous stasis underlie the pathophysiology of the hypercoagulable state of pregnancy [2]. The presentation of thromboembolism in pregnancy can be variable, including superficial or deep VTE, cerebrovascular accidents, or rare conditions such as hepatic vein thrombosis causing Budd-Chiari Syndrome (BCS). While malignancy is a frequent cause of thromboembolic disease in elderly patients, cancer is rare in pregnancy, complicating only 0.1% of all pregnancies [3]. We report a case of a pregnancy complicated by recurrent thromboembolic events including antepartum ischemic stroke and intrapartum acute BCS, ultimately due to metastatic pancreatic adenocarcinoma. This report demonstrates the diagnostic complexity presented by rare diseases in otherwise healthy young pregnant women, and we suggest a systematic approach to the evaluation for occult malignancy in pregnancy. Case A 31-year-old G2P1001 Caucasian woman at 26 weeks 2 days’ gestation presented to the emergency room with dizziness, visual changes, confusion, and aphasia. See online supplementary Figure 1 for her complete clinical course (for all online suppl. material, see www.karger.com/doi/10.1159/000487046). Her husband reported that she was acting strangely and had been complaining of “flashes of light” in her vision. She endorsed a history of narcolepsy, history of traumatic brain injury from a childhood equestrian accident, and a family history of lung cancer. She denied any personal or familial history of clotting disorders or malignancy. Her prenatal laboratory studies were within normal limits, and the pregnancy had been uncomplicated. Her vital signs and an electrocardiogram were normal, and a fetal non-stress test was reactive. The neurology team was consulted, and a brain MRI without contrast showed acute left middle cerebral artery infarct from arterial thrombus (Fig. 1a). She was admitted to the stroke service and treated with intravenous heparin. Upper and lower extremity Dopplers showed superficial thromboses but no deep vein thrombosis, raising suspicion for thrombophilia. Maternal echocardiogram with bubble study, thrombophilia panel, and antiphospholipid antibody screening were normal. Her only identifiable risk for stroke was pregnancy. She recovered completely over 2 days and was discharged on 15,000 U subcutaneous dalteparin daily. At 29 weeks, the patient presented again with “halos in her vision.” Her dalteparin level was sub-therapeutic, and a repeat brain MRI showed new scattered punctate infarcts in the right cerebellum and left parietal lobe, again consistent with arterial thrombosis (Fig. 1b). Her daltepa- 2 Gynecol Obstet Invest DOI: 10.1159/000487046 rin dose was increased and 81 mg daily aspirin was added to her regimen. She was monitored with twice-weekly non-stress tests. As pregnancy progressed, she complained of increasing low back pain with muscle spasms. At 36w2d, she was diagnosed with gestational hypertension. Twenty-four hours urine protein and complete blood count were normal, but liver enzymes were mildly elevated, including aspartate aminotransferase (AST) 54 U/L; alanine aminotransferase (ALT) 60 U/L; alkaline phosphatase 543 U/L; and total bilirubin 5.6 mg/dL. Induction of labor was initiated at 36w6d for gestational hypertension, and the patient acutely developed jaundice and dramatic hepatomegaly. Labs at that time revealed: hematocrit 33.7%; platelets 286 × 109/L; AST 50 U/L; ALT 45 U/L; alkaline phosphatase 559 U/L; total bilirubin 7.6 mg/dL (direct 4.6 mg/dL); uric acid 2.5 mg/ dL; LDH 291 U/L; INR 2.0 s; and Lipase 21 U/L. She was started on intravenous heparin, and induction of labor progressed with misoprostol, oxytocin, and artificial rupture of membranes. A right upper quadrant ultrasound during labor showed 21 cm heterogeneous hepatomegaly with nodules, decreased hepatic vein Doppler flow, and increased inferior vena cava Doppler velocity of 240 cm/s concerning for BCS (Fig. 1c). The patient delivered a healthy 3,490 g male infant with Apgars of 9 and 9 at 1 and 5 minutes. On postpartum day 1, her INR increased to 2.9 s and her total bilirubin to 9.0 mg/dL, while other labs were ammonia 47 umol/L; alkaline phosphatase 628 U/L; AST 57 U/L; ALT 50 U/L; fibrinogen 461 mg/dL. The heparin infusion was continued, and contrast-enhanced CT imaging showed thrombus with near complete occlusion of the intrahepatic portion of the inferior vena cava, middle, and right hepatic veins, multiple liver lesions favoring metastases, an ill-defined mass lesion within the pancreatic tail, and ascites (Fig. 1d). A fluoroscopicguided needle biopsy of the liver was consistent with metastatic pancreatic adenocarcinoma (CA19–9 and CK7 positive with negative neuroendocrine markers), and her serum CA19–9 was elevated at >200,000 U/mL (normal <37 U/mL). The oncology team confirmed the presumed diagnosis of Stage IV pancreatic adenocarcinoma. She received 3 cycles of palliative FOLFOX chemotherapy and was eventually discharged home to hospice care. She developed bacterial peritonitis and passed away 8 weeks after delivery. The patient’s family reviewed this report and gave consent for publication. The Colorado Multiple Institutional Review Board (Aurora, CO, USA) determined that this case report was exempt from human subjects’ research review certification. Discussion Pancreatic cancer is extremely rare in pregnancy, and only 3–4% of pancreatic cancer patients are females of reproductive age [4]. In a large Swedish population study, cancer of all endocrine glands occurred in less than 1 per 500,000 live births, with pancreatic adenocarcinoma even rarer [3]. Pancreatic cancer is almost always diagnosed at late stages and carries a poor prognosis with a 5-year survival rate <5% [5]. Improved survival of 15–20% at 5 years is possible with early diagnosis and complete resection [4]. A medline search of the English language literature from Wakefield/Masterson/Borges/Hurt Downloaded by: Leiden University Medisch Centrum 132.229.13.63 - 6/11/2018 1:13:55 PM Introduction b c d Fig. 1. A 32-year-old G2P1 presents at 26 weeks with aphasia, vi- sual changes, and confusion and 3 weeks later with recurrent visual changes. a Diffusion-weighted axial MRI with an acute left temporal lobe infarct (arrow). b Diffusion-weighted axial MRI with a smaller acute right cerebellar infarct (arrow) at 29 weeks’ gestation. c Gray-scale ultrasound of the right upper quadrant. A dominant liver metastasis is clearly visible (arrow; calipers = 1.7 cm) with diffusely heterogeneous underlying liver parenchyma. d Contrast-enhanced, axial abdominal CT scan shows hepatomegaly with multiple hypodense nodules (arrows). An ill-defined, lowdensity mass lies within the tail of the pancreas (arrowhead) concerning for pancreatic malignancy. 1954 to 2017 using the key words “pancreatic cancer/adenocarcinoma/malignancy” and “pregnancy” revealed 21 previously published cases of pancreatic adenocarcinoma in pregnancy (online suppl. Table 1). The average age at presentation for pancreatic cancer in pregnancy from these reports was 35 years (95% CI 33–37 years) and the average gestational age at diagnosis was 24 weeks (95% CI 21–27 weeks). Maternal demise occurred in 16 out of 20 (80%) cases where maternal outcomes were reported. Pancreatic cancer in pregnancy presents identically to non-pregnant patients, with abdominal pain (68%), biliary obstruction (50%), or non-specific symptoms such as weight loss, fatigue, and back pain (online suppl. Table 1) [5]. Common benign causes of abdominal pain and obstructive jaundice in pregnancy include choledocholithiasis, cholecystitis, pancreatitis, viral hepatitis, intrahepatic cholestasis of pregnancy, and preeclampsia. This overlap in symptoms combined with low provider suspicion in a typically low-risk patient population can delay diagnosis. Our patient showed mild liver enzyme abnormalities prior to induction, with preeclampsia or evolving HELLP syndrome the most likely Diagnostic Dilemma of Antepartum Stroke Gynecol Obstet Invest DOI: 10.1159/000487046 3 Downloaded by: Leiden University Medisch Centrum 132.229.13.63 - 6/11/2018 1:13:55 PM a 4 Gynecol Obstet Invest DOI: 10.1159/000487046 resection (18–22 vs. 42 months) [4]. Diagnosis in pregnancy, however, is complicated by normal physiologic changes and fetal considerations. Transabdominal ultrasound is often insufficient to evaluate the pancreas and can be obscured by bowel displaced by the gravid uterus [14]. Contrast-enhanced CT scan is the method of choice for diagnosis and staging of pancreatic tumors in nonpregnant patients [5]; however, CT is often delayed in pregnancy, considering the risks of fetal radiation exposure. Whole body MRI may be an acceptable alternative. In many reported cases of pancreatic cancer in pregnancy (online suppl. Table 1), the diagnosis was made by endoscopic ultrasound and fine-needle aspiration. Endoscopic ultrasound and fine-needle aspiration has a higher sensitivity (78–95%) and specificity (75–100%) for diagnosing pancreatic cancer than CT-fine-needle aspiration, a lower complication rate (0–2%) [15], and no fetal irradiation. Some reports have also suggested that expanded cell-free DNA panels could eventually assist with malignancy screening in asymptomatic pregnant patients [16]. Although the utility of screening for malignancy in young patients with idiopathic VTE beyond history, physical exam, and age-appropriate cancer screening is a standing question [13], earlier imaging for occult malignancy may have been beneficial in this case. However, none of the previously reported cases of pancreatic cancer in pregnancy presented with arterial thrombosis, and given her initial lack of localizing symptoms, we suspected underlying thrombophilia less concern for occult neoplasm. Failure to diagnose malignancy due to pregnancy considerations may have reduced her chances for successful early resection and prolonged survival. Using this case, and applying the literature from older nonpregnant patients with cancer, we have developed an evidencebased algorithm for the evaluation of unusual presentations of thromboembolic disease during pregnancy (Fig. 2). In summary, occult malignancy is rare but should be included on the differential for antepartum stroke or recurrent thrombosis with negative thrombophilia testing. Given that stroke-related maternal mortality is twice that of non-stroke related maternal mortality [6], cases such as this challenge the obstetrician to maintain a broad differential and consider the evaluation of rare diseases in an otherwise young and healthy patient. In an effort to mitigate maternal morbidity and mortality, the evaluation for occult malignancy in pregnancy should be pursued using an evidence-based approach like the one that we have proposed. Wakefield/Masterson/Borges/Hurt Downloaded by: Leiden University Medisch Centrum 132.229.13.63 - 6/11/2018 1:13:55 PM diagnosis. When she developed acute BCS during labor with obvious hepatomegaly and obstructive jaundice, hepatobiliary system evaluation was indicated, and postpartum CT showed a large pancreatic mass with metastases. Stroke is also rare in pregnancy and the puerperium, complicating 34 out of 100,000 deliveries [6], with 75% occurring postpartum [7]. The differential diagnosis for pregnancy-associated stroke includes preeclampsia/eclampsia, cardioembolic disease, antiphospholipid syndrome, inherited thrombophilia, and pregnancy-related hypercoagulability [7]. Other stroke risk factors include migraine headaches, hypertension, diabetes, smoking, advanced maternal age, and African American race [6]. Our patient had no strong risk factors for pregnancyassociated stroke, and her serologic evaluation for inherited or acquired thrombophilia was normal. In retrospect, several aspects of this case could have increased the suspicion for malignancy-associated stroke. First, pregnancy-associated stroke in the second trimester is rare, occurring only in 3% of cases [7]. In nonpregnant patients with cancer, malignancy-associated stroke is common, found in 15% of oncology patients at autopsy [8]. Second, the pattern of small arterial infarcts in multiple vascular territories seen in this patient is associated with paraneoplastic hypercoagulability [9]. While the association between malignancy and arterial thrombosis is not as well established, the relationship between malignancy and venous thrombosis is clear with occult malignancy diagnosed in 10% of patients with unprovoked VTE [10]. Pancreatic neoplasms are associated with a particularly high incidence of VTE between 10 and 50% [11]. Combined arterial and VTE, though rare, is also a reported presentation of metastatic pancreatic adenocarcinoma [12]. Therefore, a patient with unexplained recurrent thromboembolic phenomena, even in pregnancy, should be thoroughly evaluated for malignancy. The most appropriate evaluation for occult malignancy in young, low-risk pregnant women has not been established. Evaluation of idiopathic VTE in an older cohort (mean age 66 years) using imaging and serum biomarkers, identified neoplasia with 93% sensitivity but did not produce a significant survival benefit [13]. Nonetheless, this approach led to a definitive cancer diagnosis 10 months earlier and at an earlier stage. Early diagnosis of pancreatic malignancy is imperative because survival benefit is only achieved with surgical resection. One retrospective study suggested that patients under 45 years of age have twofold increased survival with early surgical Pregnant or within 6 weeks postpartum Venous thromboembolism Arterial thromboembolism Initial diagnostic workup Initial diagnostic workup • H and P, basic labs (CBC, CMP, coags) • Inherited thrombophilia testing: ∘ Antithrombin ∘ Protein C/S ∘ Factor V leiden ∘ Prothrombin G20210A mutation • APLAS testing: ∘ Lupus anticoagulant ∘ Antithrombin antibodies ∘ Anti-β2-glycoprotein antibodies • H and P, basic labs + D-Dimer • APLAS testing • Echocardiogram • Age-appropriate cancer screening ∘ PAP smear if >21 year ∘ Mammogram if >40 year ∘ Chest X-ray if smoking history • Initiate therapeutic anticoagulation with LMWH Positive workup Positive workup LMWH per ACOG guidelines Ischemic stroke Negative workup • Age-appropriate cancer screening • Initiate therapeutic anticoagulation with LMWH Brain MRI* Recurrent thromboembolism Multiple small infarcts Confirm therapeutic anticoagulation Subtherapeutic Serum D-Dimer*† Single infarct <4,000 ng/mL >4,000 ng/mL Therapeutic Symptom-focused screening for occult malignancy Platelet count <150,000/µL or >50% decrease • Pulmonary – chest X-ray • Gastrointestinal-hemoccult, gastroscopy, AUS, colonoscopy • Hepatobiliary – EUS, ERCP Normal Negative workup with continued suspicion for occult malignancy Serum D-Dimer*† <4,000 ng/mL Symptom-focused screening for occult malignancy >4,000 ng/mL Full-body screening for occult malignancy • Tumor markers-CEA, CA19–9, α-FP, CA-125 • Extensive imaging-CT, PET/CT, or MRI Negative workup with continued suspicion for occult malignancy Fig. 2. Diagnostic algorithm for occult malignancy in pregnancy. We used current ACOG recommendations [17, 18] for thromboembolism workup and revised/supplemented with recommendations from studies examining nonpregnant patients. The algorithm is modeled on the broad evaluation of malignancy proposed for nonpregnant patients [13], moving from simple blood test biomarkers, which may be less sensitive during pregnancy [19, 20] but useful to rule out cancer, to more extensive imaging and invasive procedures with greater sensitivity in patients with higher suspicion of malignancy. The final algorithm was developed by radiol- ogy and obstetrics specialists and reviewed by external experts in maternal fetal medicine and gynecologic oncology. This expert opinion, evidence-based guide has not been validated in prospective clinical trials. * Guo et al. [20]. † Han et al. [19]. H and P, history and physical exam; CBC, complete blood count; CMP, comprehensive metabolic panel; APLAS, antiphospholipid anti syndrom; LMWH, low-molecular weight heparin; HIT, heparin induced thrombocytopenia; AUS, abdominal ultrasound; ERCP, endoscopic retrograde cholangiopancreatetography; EUS, endoscopic ultrasound; PET, positron emission tomography. Diagnostic Dilemma of Antepartum Stroke Gynecol Obstet Invest DOI: 10.1159/000487046 5 Downloaded by: Leiden University Medisch Centrum 132.229.13.63 - 6/11/2018 1:13:55 PM Increase LMWH dose Evaluate for HIT Other thrombosis Acknowledgments Disclosure Statement We thank Drs. Donald Dudley, MD and Susan Modesitt, MD for their assistance in reviewing this manuscript and revising the diagnostic algorithm. The authors report no conflicts of interest or sources of financial support. References 6 Gynecol Obstet Invest DOI: 10.1159/000487046 9 Schwarzbach CJ, Schaefer A, Ebert A, Held V, Bolognese M, Kablau M, Hennerici MG, Fatar M: Stroke and cancer: the importance of cancer-associated hypercoagulation as a possible stroke etiology. Stroke 2012;43:3029–3034. 10 Carrier M, Le Gal G, Wells PS, Fergusson D, Ramsay T, Rodger MA: Systematic review: the Trousseau syndrome revisited: should we screen extensively for cancer in patients with venous thromboembolism? Ann Intern Med 2008;149:323–333. 11 Khorana AA, Fine RL: Pancreatic cancer and thromboembolic disease. Lancet Oncol 2004; 5:655–663. 12 Majumder S, Thom T, Dasanu CA: Catastrophic arteriovenous thromboembolism as initial manifestation of pancreatic cancer. JOP 2012;13:231–234. 13 Piccioli A, Lensing AW, Prins MH, Falanga A, Scannapieco GL, Ieran M, Cigolini M, Ambrosio GB, Monreal M, Girolami A, Prandoni P; SOMIT Investigators Group: Extensive screening for occult malignant disease in idiopathic venous thromboembolism: a prospective randomized clinical trial. J Thromb Haemost 2004;2:884–889. 14 Onuma T, Yoshida Y, Yamamoto T, Kotsuji F: Diagnosis and management of pancreatic carcinoma during pregnancy. Obstet Gynecol 2010;116(suppl 2):518–520. 15 Yoshinaga S, Suzuki H, Oda I, Saito Y: Role of endoscopic ultrasound-guided fine needle as- piration (EUS-FNA) for diagnosis of solid pancreatic masses. Dig Endosc 2011;23(suppl 1):29–33. 16 Amant F, Verheecke M, Wlodarska I, Dehaspe L, Brady P, Brison N, Van Den Bogaert K, Dierickx D, Vandecaveye V, Tousseyn T, Moerman P, Vanderstichele A, Vergote I, Neven P, Berteloot P, Putseys K, Danneels L, Vandenberghe P, Legius E, Vermeesch JR: Presymptomatic identification of cancers in pregnant women during noninvasive prenatal testing. JAMA Oncol 2015;1:814–819. 17 James A; Committee on Practice BulletinsObstetrics: Practice bulletin no. 123: thromboembolism in pregnancy. Obstet Gynecol 2011;118:718–729. 18 American College of Obstetricians and Gynecologists Women's Health Care Physicians: ACOG practice bulletin No. 138: inherited thrombophilias in pregnancy. Obstet Gynecol 2013;122:706–717. 19 Han D, ó Hartaigh B, Lee JH, Cho IJ, Shim CY, Chang HJ, Hong GR, Ha JW, Chung N: Impact of D-dimer for prediction of incident occult cancer in patients with unprovoked venous thromboembolism. PLoS One 2016; 11:e0153514. 20 Guo YJ, Chang MH, Chen PL, Lee YS, Chang YC, Liao YC: Predictive value of plasma (D)dimer levels for cancer-related stroke: a 3-year retrospective study. J Stroke Cerebrovasc Dis 2014;23:e249–e254. Wakefield/Masterson/Borges/Hurt Downloaded by: Leiden University Medisch Centrum 132.229.13.63 - 6/11/2018 1:13:55 PM 1 Ren W, Li X, Jia J, Xia Y, Hu F, Xu Z: Prevalence of budd-chiari syndrome during pregnancy orp: a systematic review and meta-analysis. Gastroenterol Res Pract 2015;2015:839875. 2 Grear KE, Bushnell CD: Stroke and pregnancy: clinical presentation, evaluation, treatment, and epidemiology. Clin Obstet Gynecol 2013;56:350–359. 3 Andersson TM, Johansson AL, Fredriksson I, Lambe M: Cancer during pregnancy and the postpartum period: a population-based study. Cancer 2015;121:2072–2077. 4 Duffy A, Capanu M, Allen P, Kurtz R, Olson SH, Ludwig E, Klimstra DS, O’Reilly EM: Pancreatic adenocarcinoma in a young patient population – 12-year experience at Memorial Sloan Kettering Cancer Center. J Surg Oncol 2009;100:8–12. 5 Hidalgo M: Pancreatic cancer. N Engl J Med 2010;362:1605–1617. 6 James AH, Bushnell CD, Jamison MG, Myers ER: Incidence and risk factors for stroke in pregnancy and the puerperium. Obstet Gynecol 2005;106:509–516. 7 Miller EC, Yaghi S, Boehme AK, Willey JZ, Elkind MS, Marshall RS: Mechanisms and outcomes of stroke during pregnancy and the postpartum period: a cross-sectional study. Neurol Clin Pract 2016;6:29–39. 8 Graus F, Rogers LR, Posner JB: Cerebrovascular complications in patients with cancer. Medicine (Baltimore) 1985;64:16–35.