A 68-Year-Old Man With Recurrent Pulmonary Embolism Resulting in Sudden Death

CASE REPORT

A 68-year-old white male with a history of alcohol abuse, depression, fatty liver, generalized anxiety disorder, major depression, neurofibromatosis type 1 (NF-1), COPD, hypertension, incomplete right bundle branch block, and pulmonary embolism (PE) 1 year prior, presented with a 1-day history of severe lethargy. The patient had completed 11 months of warfarin treatment 2 weeks before presentation, and his current home medications included lisinopril (20 mg daily), tiotropium inhaler (18 μg daily), escitalopram (20 mg daily), bupropion (150 mg twice daily), and alprazolam (0.5 mg twice daily). He denied shortness of breath, chest pain, headaches, tremors, seizure activity, or loss of consciousness. His last alcoholic drink was 4 days before presentation. Family history was significant for breast cancer in his mother. At admission, he was afebrile, with a blood pressure of 139/98 mm Hg, a regular heart rate of 118 beats per minute and a respiratory rate of 24 per minute. His right lower extremity was warm to the touch, compared with the left lower extremity. The rest of his physical examination was unremarkable. Electrocardiography showed sinus tachycardia, old right bundle branch block, with no new ST changes or T-wave inversions. Initial blood tests demonstrated increased white count of 15,800 with a left shift of neutrophils at 89% and INR of 1.17. A computed tomographic (CT) scan of the head without contrast performed in the emergency department did not reveal any acute intracranial process. A Doppler study of the lower extremities revealed deep vein thrombosis (DVT) involving the right lower extremity from the level of the popliteal vein to the trifurcation.

The patient was started on warfarin and enoxaparin, admitted to the medical floor, and scheduled for a CT angiogram of the chest. Over the course of the next 12 hours, he suddenly started having some chest pain, became hemodynamically unstable, went into cardiac arrest, and could not be resuscitated. He was pronounced dead with a clinical diagnosis of PE.

Autopsy confirmed the clinical diagnosis and showed a large pulmonary thromboembolus at the bifurcation of the pulmonary trunk and multiple smaller bilateral PEs associated with marked congestion, edema, and areas of infarction. Of particular interest, autopsy also showed a well-differentiated periampullary duodenal adenocarcinoma, invading through the muscle wall into adjacent fat (Figures 1 and 2).

Figure 1.

Photograph of pathologic specimen showing periampullary duodenal adenocarcinoma.

Figure 2.

Microphotograph showing periampullary duodenal adenocarcinoma (magnification, 20×).

DISCUSSION

The term periampullary carcinoma is commonly used to describe a heterogeneous group of cancers arising from the head of the pancreas, the distal common bile duct, and the duodenum.¹ Periampullary cancer accounts for more than 30,000 cancer-related deaths per year in the United States.² Of all periampullary neoplasia, duodenal cancer is the least common (7% of periampullary malignancies) after tumors of the pancreas (62%), ampulla (19%), and bile ducts (12%).³ More than 95% of all duodenal periampullary cancers are mucin-producing adenocarcinomas.³ Duodenal adenocarcinoma may be present in younger patients, but most patients are typically within the 6th to 8th decades of life, with no particular gender predominance.⁴ The most common presenting signs and symptoms are abdominal pain, iron-deficiency anemia, weight loss, nausea, vomiting, and obstructive jaundice.⁵ The mainstay of diagnosis is either upper gastrointestinal tract radiographs or endoscopy. CT and endoscopic ultrasound are often used to determine tumor stage and should enable differentiation of primary duodenal carcinoma from the other periampullary tumors invading the duodenum.⁶

NF-1 is an autosomal inherited disorder, with an incidence of about 1 per 3000 births and with no gender predilection.⁷ The classic triad of symptoms is: café-au-lait spots (brown skin pigmentation), cutaneous neurofibromas, and neoplasms of the nervous system. Malignancies are found in 3% to 15% of patients, with malignant peripheral nerve sheath tumors reported most commonly. Other NF1-associated tumors include rhabdomyosarcomas, gastrointestinal stromal tumors (GISTs), pheochromocytomas, and ganglioneuromas. Gastrointestinal involvement, usually in the form of tumors of neural crest origin, is seen in approximately 25% of cases.⁷ An association between neurofibromatosis and an increased risk of epithelial periampullary tumors has also been reported.⁷ In three of four cases reviewed by Jones and Marshall,⁸ the patients were found to have asymptomatic, benign NF-1-related tumors in addition to their symptomatic duodenal adenocarcinomas.

The connection between venous thromboemboli and malignancy has long been recognized. Occasionally, DVT and PE may be the presenting signs of a previously undetected tumor. However, how often this happens has been the subject of some debate. In a prospective study from Sweden of patients with DVT, Nordstrom et al¹⁰ found a significantly increased rate of cancer diagnosis in the first 6 months after the diagnosis of DVT, when compared with the general population. Sorensen et al¹¹ found a smaller but still significant increased risk in patients with DVT and PE in the first year after diagnosis and found the risk to be particularly associated with cancers of the pancreas, ovary, and brain and in primary hepatic malignancies.

At autopsy, the patient presented in this report had numerous cutaneous neurofibromas. His lungs showed a large pulmonary thromboembolus at the bifurcation of the pulmonary trunk with associated pulmonary infarcts. These emboli almost certainly originated from thrombi in the deep leg veins. PE represents the most likely immediate cause of death. The patient did not have any obvious risk factors for repeated episodes of DVT and PE. Specifically, he was not obese, he was not bedbound or known to be unduly sedentary, and he had no history of recent trauma or surgery. His known medications did not confer any increased risk of thrombosis. There is no known family history of coagulopathy, and it is not known if the patient had a genetic predisposition toward thrombosis. At autopsy, however, an unsuspected duodenal adenocarcinoma was found that had invaded the muscularis propria. The tumor did not obstruct the ampulla and apparently produced no symptoms.

Given the clinical history and anatomic findings, it seems likely that the patient's neurofibromatosis predisposed him toward the development of duodenal adenocarcinoma. This occult adenocarcinoma, in turn, increased his risk of venous thrombi and the PE that resulted in his death.