Appendiceal adenocarcinoma presenting as venous thromboembolism: an unusual presentation of a rare carcinoma.

To the Editor: A 63-year-old man presented to his primary care provider 1 week after the onset of severe, bilateral, radiating leg pain. His medical history was unremarkable and review of systems was otherwise negative. Physical examination revealed bilateral lower extremity swelling, and Doppler ultrasound demonstrated bilateral lower extremity deep vein thrombosis and right upper extremity superficial thrombosis. Abdominal examination was unremarkable, and a hypercoagulability panel, including protein C and S, prothrombin 20210, factor V Leiden, and lupus anticoagulant levels, were all within normal limits. Abdominal CT was obtained at an outside facility as a result of concern for occult malignancy associated with the venous thromboembolism (VTE). The study revealed a dilated appendix and the patient was referred to our institution for further care. Three days later, the patient presented to the emergency department with dull right lower quadrant pain, and a repeat abdominal CT revealed a large, inflamed appendix with free fluid in the pelvis (Fig. 1). The patient was taken to the operating room emergently and was noted to have a thickened, inflamed appendix and diffuse peritoneal carcinomatosis. He underwent a right hemicolectomy and resection of a portion of the abdominal wall and peritoneum. The specimen contained a moderately differentiated appendiceal adenocarcinoma measuring 7.0 cm in greatest dimension arising from a tubulovillous adenoma at the tip of the appendix, and he was diagnosed with Stage IV (T3, N2, M1) disease. The patient's postoperative course was uncomplicated and he was discharged home on postoperative Day 4. Fig. 1 CT scan demonstrating a grossly abnormal appendix with thickened enhancing wall measuring almost 3 cm transverse. A small amount of free fluid is seen within the pelvis. Treatment with cytoreductive surgery (CS) and hyperthermic intraperitoneal chemotherapy (HIPEC) was discussed with the patient and multiple referral centers, but as a result of his history of VTE and subsequent anticoagulation, he was not felt to be a candidate at that time and the decision was made to treat with systemic FOLFOX chemotherapy (folinic acid, fluorouracil, and oxaliplatin). Tumor markers were measured 2 and 4 weeks postoperatively, and carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) levels rose from 9.4 ng/mL and 285 U/mL to 47 ng/mL and 1882 U/mL, respectively. Four weeks after discharge, the patient was readmitted with right lower quadrant pain of 1-week duration, and abdominal CT revealed ascites, carcinomatosis, and small bowel obstruction. The patient was initially treated conservatively but did not improve and underwent a repeat laparotomy, which revealed diffuse carcinomatosis with multiple areas of obstruction. A small bowel resection with primary anastomosis was performed, and a gastrostomy tube was placed. Postoperatively, the patient developed an inferior myocardial infarction. With his aggressive disease and poor functional status, the patient was placed on supportive care after discussions with his family and died the next day. Appendiceal adenocarcinoma is a rarely diagnosed carcinoma with most cases diagnosed incidentally during operations for presumed appendicitis. As a result of the often incidental nature of diagnosis, there are no established guidelines for preoperative diagnostic evaluation. In our case, multiple VTEs secondary to a hypercoagulable state heralded the diagnosis of this occult malignancy. Current guidelines recommend that all noncarcinoid appendiceal tumors should be treated with right hemicolectomy, yet right hemicolectomy is not always performed as a result of the incidental nature of the diagnosis. Recent studies have questioned whether this should still be considered the definitive treatment when peritoneal dissemination is present. Gonzalez-Moreno and Sugarbaker found in a series of 501 patients with appendiceal adenocarcinoma and peritoneal dissemination that there was no survival benefit associated with right hemicolectomy over appendectomy when patients received both CS and HIPEC. However, right hemicolectomy is still required in some cases in which the primary tumor involves the colon, inadequate margins are obtained, or positive lymph nodes are present.1 HIPEC, also known as heated intraoperative in-traperitoneal chemotherapy or intraperitoneal chemo-hyperthermia, is now coupled with CS in patients with peritoneal spread of appendiceal cancer. This treatment involves the introduction of heated chemotherapy, typically using mitomycin C, into the abdominal cavity after resection of all gross disease, which allows for diffusion of a high concentration of chemotherapy directly into tumor implants. Aggressive cytoreduction and peritoneal stripping remove all macroscopic disease, theoretically leaving only microscopic tumor implants, which are vulnerable to the chemo-therapeutic agent. For patients who recur, additional removal of peritoneal disease is sometimes feasible and has been associated with an improved survival unless the indication for operation is intestinal obstruction.2 Careful workup is required before patient selection for CS and HIPEC. Recommended preoperative tests include colonoscopy and CT of the chest, abdomen, and pelvis to accurately stage the disease burden. CS and HIPEC have been shown to exhibit a benefit in disease-specific and progression-free survival over systemic chemotherapy in patients with peritoneal carcinomatosis in a randomized trial of patients with colorectal and appendiceal carcinoma, although the role of these therapies is not clearly established for primary colorectal carcinoma.3 The role of systemic chemotherapy in the treatment of appendiceal adenocarcinoma is not well defined, and the paradigm of colorectal cancer treatment is generally followed. Thus, FOLFOX is generally used, although evidence is limited and no prospective, randomized trials exist for the treatment of appendiceal cancer. Evidence for the use of postoperative radiation is also lacking. CEA and CA19-9 levels have been demonstrated to correlate with tumor recurrence.4 Although levels of either marker are not always elevated in those with recurrent disease, normal levels are a valuable aid because they indicate an improved prognosis.4 Monitoring tumor markers after treatment is an important aspect of care, although there are no specific guidelines on frequency; at our institution, we typically follow patients every 3 months. We report on a case of appendiceal adenocarcinoma with peritoneal carcinomatosis manifesting as venous thromboembolism and treated at our institution over the past year. Appendiceal adenocarcinoma is difficult to diagnose preoperatively, and therefore it is recommended that when there is intraoperative suspicion or pathologic confirmation of disease that right hemicolectomy is performed. If peritoneal dissemination is evident, patients should be referred to a peritoneal surface malignancy center. Evidence for additional treatment with systemic chemotherapy is lacking at this point, but principles used in the management of advanced colorectal carcinoma are often used. Finally, it is important to be aware of the risk of thromboembolic disease in these patients, which is increased by chemotherapy and extended immobility secondary to major cancer surgery. Thromboembolic prophylaxis must be balanced with treatment options to ensure benefit from the new modalities, and further research into the efficacy and sequence of treatments may clarify these issues.