Improved metastatic uterine papillary serous cancer outcome with treatment of mast cell activation syndrome.

The case: In May 2010, a 71-year-old woman not on hormone replacement therapy presented with uterine bleeding. Endometrial biopsy was foiled by severe cervical stenosis. Dilation & curettage revealed complex hyperplasia with atypia, focal clear-cell features, and endocervicitis. Endometrial intraepithelial carcinoma was suspected. Frozen section analysis from hysterectomy and bilateral salpingo-oophorectomy revealed noninvasive grade 1 endometrial cancer. Thus, lymphadenectomy was not performed. However, final pathology showed metastatic uterine papillary serous adenocarcinoma (UPSC) with bilateral tubo-ovarian micrometastases. Additional testing showed microsatellite instability but not Lynch syndrome. Positron emission and computed tomography (PET/CT) in August 2010 demonstrated hypermetabolic adenopathy, including a 1.1-cm para-aortic node (fluorodeoxyglucose [FDG] standardized uptake value [SUV] of 3.4), a subcentimeter aortocaval node (SUV, 2.4), and a 1.0-cm node inferior to the aortic bifurcation (SUV, 2.7). Cancer antigen 125 (CA125) level was 55.9 U/mL. The patient declined full surgical staging, including pelvic/ para-aortic lymphadenectomy. She began carboplatin and paclitaxel (CP), which was well tolerated until superficial venous thrombosis of the right distal great saphenous and right small saphenous veins during cycle 4. Warfarin was started. Restaging PET/CT in December 2010 after cycle 6 demonstrated progression of prior metastatic disease (multiple para-aortic nodes up to 1.2 cm, with SUV of 8.6) and new metastatic disease (external iliac adenopathy up to 0.9 cm, with SUV of 4.7; and paratracheal adenopathy up to 1.3 cm, with SUV of 4.3). She was started on salvage paclitaxel, doxorubicin, and cisplatin (TAP). In light of her son’s alleged protein S deficiency, she was referred for hematologic consultation; only a modest lupus anticoagulant level was found. Anticoagulation was switched to enoxaparin because of an unstable warfarin response. She was more symptomatic with TAP, reporting abdominal bloating, presyncopal episodes and palpitations (worst in each cycle’s second week, once she was off dexamethasone), soaking sweats, nausea, polyuria, polydipsia, grade 1 peripheral neuropathy, left hip pain on movement, heartburn, constipation, fatigue, and dyspnea, all of which progressed through treatment. Post–cycle 3 PET/CT in March 2011 showed new subpectoral adenopathy (1.7 cm; SUV, 8.2) and a mixed response at other sites (eg, paraaortic adenopathy up to 1.0 cm, SUV of 3.6; paratracheal adenopathy up to 1.5 cm, SUV of 3.3). Diverticulitis in the sigmoid colon was seen and was treated with amoxicillin/clavulanic acid. Abdominal pain improved somewhat. The CA-125 level, which had decreased after the first CP cycle to 24.2 U/mL, was now 15.3 U/mL. TAP was continued. Post–cycle 5 PET/CT in May 2011 again showed a mixed response (eg, subpectoral adenopathy of 1.2 cm × 0.7 cm, SUV of 1.1; paratracheal adenopathy of 1.5 cm, SUV of 3.5; para-aortic adenopathy of 0.6 cm in the short axis, SUV of 1.0). Diverticulitis had resolved. CA-125 reached its lowest level, at 6.9 U/mL, after cycle 7. Post–cycle 8 PET/CT in August 2011 showed minor further response (subpectoral adenopathy of 0.3 cm in the short axis, SUV of 0.6; paratracheal adenopathy of 1.5 cm, SUV of 2.2; para-aortic adenopathy of 0.5 cm in the short axis, SUV of 0.9). Chemotherapy was stopped. Medroxyprogesterone (MP) at 40 mg twice daily was started. The patient soon noticed worsened fatigue. During evaluation of presyncope in August 2011, she reported many chronic issues. These included hot flashes; chills; migratory pruritus; mild visual anomalies; excessive lacrimation, chronic coryza, and postnasal drip; heartburn; episodic documented hypotension; and life-long unprovoked episodes of hypomania. Mast cell activation disease (MCAD) was considered as a unifying diagnosis. Testing was delayed, but she began a full histamine blockade (famotidine, 40 mg twice daily, and loratadine, 10 mg twice daily); also, enoxaparin was stopped and daily aspirin was increased from 81 mg to 325 mg. Her symptoms all resolved. A month later she stopped aspirin and antihistamines for mast cell (MC) mediator testing. Her symptoms all immediately returned. After testing, she resumed aspirin and antihistamines, and she re-achieved complete remission of her symptoms within a week. Her serum tryptase level was normal, but her serum prostaglandin D2 (PGD2) level was mildly elevated (128 pg/mL [normal, 35–115 pg/mL]), her plasma heparin level was mildly elevated (anti–factor Xa, 0.040 U/mL [normal, 0.000–0.020 U/mL]), and her factor VIII level was moderately elevated (273% [normal, 50% to 150%]). In view of the clinical history consistent with chronic aber1Division of Hematology/Oncology, Medical University of South Carolina, Charleston, South Carolina 2Department of Pathology, Medical University of South Carolina 3Department of Radiology, Medical University of South Carolina 4Division of Gynecologic Oncology, Medical University of South Carolina lAWREncE B. AFRIn, MD1 lAURA S. SPRUIll, MD, PhD2 STEPHEn I. ScHABEl, MD3 JEnnIFER l. yOUng-PIERcE, MD4