The nodal spread caused ob- struction in lymph flow, leading to chylothorax and chyluria. Chy- luria results from chyle (lymph and triglyceride in an emulsion) in.
Tolaney et al
as a result of lymph node metastases from a malignant mesothelioma of the tunica vaginalis testis. Since its original description in 1957, fewer than 80 cases of mesothelioma of the tunica vaginalis have been reported.3 The major symptom is enlargement of the scrotum, which may develop within several months.2,3 Ultrasound of the scrotum can aid in the diagnosis, but time sampling is mandatory.2 There are three histologic types: epithelial, sarcomatous, and mixed. The most frequent occurring epithelial type has a predominant tubulopapillary growth pattern. The histologic type combined with a positive cytokeratin 5, calretinin, immunohistochemic staining establish the definitive diagnosis.2,3 Once the diagnosis is performed, staging should include CT scans of the chest and abdomen.2 For localized testicular mesotheliomas, first-line therapy should be radical orchiectomy. Although primary treatment may not be curative, local recurrence is reduced compared with hydrocele wall resection.2,3 In one review, 14.9% of patients had disseminated disease, mostly with lymph node metastases.2 Another review recommended inguinal lymphadenectomy to reduce local and distant metastases.3 Active drugs for pleural and peritoneal mesothelioma include cisplatin and permetrexed, which might also be effective for treatment of tunica vaginalis mesothelioma. Our patient developed mediastinal and abdominal lymph node and liver metastases. The nodal spread caused obstruction in lymph flow, leading to chylothorax and chyluria. Chyluria results from chyle (lymph and triglyceride in an emulsion) in the urine due to obstruction between intestinal lymphatics and (or) thoracic duct leading to rupture of renal lymphatics into renal tubules. The differential diagnosis includes filariasis, tuberculosis, pyogenic infections, and malignant disease, especially Kaposi’s sarcoma. In 1990, a case report described a 42-year-old woman with chylous ascites, caused by lymph node metastases from a pleural mestothelioma.5 We believe our patient developed lymph node metastases from the malignant mesothelioma of the tunica vaginalis. Editor’s Note Mesothelioma of the tunica vaginalis is rare enough, but chyluria (white urine) is very unusual. Other abnormal colors of urine include orange (bilirubin pigments), red (hematuria, heme pigment, or adriamycin excretion), black (melanin from metastatic melanoma), brown (rectovesicle fistula), blue or blue-green (methemoglobinuria or mitoxantrone excretion), and probably rare other colors.
5. Scully R, Mark E, McNeely W, et al: Case records of the Massachusetts General Hospital. N Engl J Med 323:659-667, 1990
DOI: 10.1200/JCO.2006.07.6596 ■ ■ ■
Authors’ Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
Pneumocystis Carinii Pneumonia During Dose-Dense Chemotherapy for Breast Cancer A 52-year-old premenopausal woman with a T2N1 invasive ductal carcinoma of the right breast presented with fever and neutropenia. Two months before admission, she began chemotherapy with doxorubicin, 60 mg/m2, and cyclophosphamide, 600 mg/m2, given every 2 weeks, with pegfilgrastim support. She received antiemetics with each cycle that included 3 days of dexamethasone at 4 milligrams given twice daily. She received three cycles without difficulty, and before the fourth cycle, experienced a fever to 101.3°F accompanied by a nonproductive cough. She had no evidence of neutropenia, and her fevers resolved spontaneously, so she was treated with her fourth cycle. Three days after receiving her fourth cycle, she developed a fever, was evaluated as an outpatient, found to have a normal neutrophil count, and was discharged to home. A dry cough persisted, and 9 days after her fourth cycle of chemotherapy, she presented to an outside hospital with a fever and an absolute neutrophil count of 800/mm3. An initial chest x-ray was normal, and she was admitted and started on empiric ceftazidime, then cefipime, and then gatifloxacin and azithromycin, due to persistant fevers. A follow-up chest x-ray revealed infiltrates involving the left upper lobe, right upper lobe, and right lower lobe. Eighteen days after her fourth cycle of chemotherapy, she was transferred to our hospital for further evaluation. On admission, she was started on broad spectrum antibiotics with ceftazidime, vancomycin, and levoquin. A computed tomography scan of the chest revealed extensive air space opacification with air bronchograms and septal thickening (Fig 1). Nasal swabs were negative for adenovirus, influenza A and B, and respiratory syncytial virus, urine was negative for Legionella antigen, and serum was negative for parainfluenza antigen and Mycoplasma. An HIV antibody was negative, and a CD4 count was 485 mm3. She underwent bronchoscopy and bronchial alveolar
Marjan J. van Apeldoorn, Cees Rustemeijer, and Bert J. Voerman Department of Internal Medicine, Ziekenhuis Amstelland, Amstelveen, the Netherlands
Johannes Peterse Department of Pathology, Netherlands Cancer Institute Anthony van Leeuwen Hospital, Amsterdam, the Netherlands © 2006 by American Society of Clinical Oncology
REFERENCES 1. Hassan R, Alexander R: Nonpleural mesotheliomas: Mesothelioma of the peritoneum, tunica vaginalis, and pericardium. Hematol Oncol Clin North Am 19:1067-1087, 2005 2. Plas E, Riedl C, Pfluger H: Malignant mesothelioma of the tunica vaginalis testis. Cancer 83:2437-2446, 1998 3. Spiess P, Tuziak T, Kassouf W, et al: Malignant mesotheliomas of the tunica vaginalis. Urology 66:397-401, 2005 4. Antman K, Hassan R, Eisner M, et al: Update on malignant mesothelioma. Oncology 19:1301-1316, 2005 5330
Fig 1. JOURNAL OF CLINICAL ONCOLOGY
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Diagnosis in Oncology
lavage was positive for Pneumocystis carinii pneumonia (PCP). She was treated with bactrim and prednisone, and had improvement in her symptoms of shortness of breath, and a computed tomography scan of her chest showed resolution of the extensive air-space opacification. PCP is predominantly seen in patients with AIDS, hematologic malignancies, and in transplant recipients. Cases of PCP in patients with breast cancer are rare, and previously described patients who developed PCP were receiving substantial corticosteroid therapy, or high-dose chemotherapy with peripheral blood stem-cell transplantation. We describe here the first reported case of PCP occurring in a patient receiving dose-dense every 2 week adjuvant chemotherapy, using doxorubicin and cyclophosphamide followed by paclitaxel. In the last year, we have had one other patient also develop PCP after her fourth cycle of dose-dense chemotherapy. PCP is a common opportunistic infection is those infected with HIV with CD4 counts less than 200 cells/mm3, but is less common in patients with cancer.1 In a retrospective review from Memorial Sloan-Kettering Cancer Center (New York, NY), the majority of cases of PCP were found in patients with hematologic malignancy.2 Corticosteriods are thought to be one of the strongest predisposing factors to the development of PCP in patients with cancer,3 with 87% of cases of PCP in this series occurring in patients receiving steroids. The median duration of therapy with corticosteroids before the onset of infection with PCP was about 12 weeks. Both of our patients had onset of symptoms approximately 8 weeks after initiating corticosteroids, which were given for several days at the beginning of each cycle of treatment. Most of the studies looking at the association of corticosteroid use and the risk of PCP involved continuous dosing of steroids, making it is difficult to know if the intermittent doses our patients received over four cycles placed them at risk for PCP. Reduced CD4 lymphocyte number is also thought to predispose patients to PCP.4,5 Lymphocyte depletion in patients receiving chemotherapy may correlate with the frequency and intensity of the dose.6 As the use of dose-intensive chemotherapy regimens has increased, there has been an increase in the incidence of opportunistic infections in patients with cancer.7 This suggests that the dose-intensive chemotherapy regimens, such as the dose-dense chemotherapy, may induce more frequent or severe lymphopenia. The use of filgrastim in the every 2-week dosing used in Cancer and Leukemia Group B trial 9741 results in a significant decrease in the incidence of grade 4 neutropenia and fewer treatment delays due to hematologic toxicity.8 More recently, it has become common to use pegfilgastrim in place of filgrastim because of the ease of administration and the apparent safety of the approach.9 While growth factor support has allowed for shorter intervals between cycles with adequate recovery of neutrophils, adequate lymphocyte reconstitution may not occur. When Mackall et al7 evaluated lymphocyte recovery in patients receiving dose-intensive chemotherapy, they found that lymphocyte populations did not recover before the administration of successive cycles of chemotherapy, despite having adequate recovery of neutrophils and platelets. This study involved too few patients to determine whether opportunistic complications directly correlated with the degree of lymphopenia. It has been suggested that the clinical course and outcome of PCP in patients with malignancy may be more fulminant than in patients with HIV, with mortality rates approaching 50%.2 In order to prevent PCP, some have recommended wider use of prophylaxis.10 In
patients with malignancy, current recommendations are to give prophylaxis to those with acute lymphocytic leukemia, patients undergoing bone marrow transplantation, and those receiving corticosteroid therapy with ⱖ 20 mg prednisolone equivalents for ⱖ 1 month.11 There are also some who suggest prophylaxis for immunocompromised patients without HIV with CD4 counts less than 300 cells/mm3.12 Our two examples demonstrate that PCP can occur in patients receiving dose-dense chemotherapy for breast cancer. While dosedense chemotherapy has been shown to improve disease-free and overall survival in those with node-positive breast cancer,13 further study is needed to investigate whether the shortened intervals between cycles may place patients at risk for lymphocyte depletion and increased incidence of opportunistic infections. Prospective assessment of the impact of dose-dense chemotherapy on lymphocyte counts and lymphocyte subsets is ongoing.
Sara M. Tolaney, Ann H. Partridge, Rochelle G. Sheib, Harold J. Burstein, and Eric P. Winer Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA © 2006 by American Society of Clinical Oncology
REFERENCES 1. Sepkowitz KA: Opportunistic infections in patients with and patients without Acquired Immunodeficiency Syndrome. Clin Infect Dis 34:1098-1107, 2002 2. Sepkowitz KA, Brown AE, Telzak EE, et al: Pneumocystis carinii pneumonia among patients without AIDS at a cancer hospital. JAMA 267:832-837, 1992 3. Yale SH, Limper AH: Pneumocystis carinii pneumonia in patients without acquired immunodeficiency syndrome: Associated illness and prior corticosteroid therapy. Mayo Clin Proc 71:5-13, 1996 4. Kane GC, Troshinsky MB, Peters SP, et al: Pneumocystis carinii pneumonia associated with weekly methotrexate: Cumulative dose of methotrexate and low CD4 cell count may predict this complication. Respir Med 87:153-155, 1993 5. Siminski J, Kidd P, Phillips GD, et al: Reversed helper/suppressor T-lymphocyte ratio in bronchoalveolar lavage fluid from patients with breast cancer and Pneumocystis carinii pneumonia. Am Rev Respir Dis 143:437-440, 1991 6. Kulke MH, Vance EA: Pneumocystis carinii pneumonia in patients receiving chemotherapy for breast cancer. Clin Infect Dis 25:215-218, 1997 7. Mackall CL, Fleisher TA, Brown MR, et al: Lymphocyte depletion during treatment with intensive chemotherapy for cancer. Blood 84:2221-2228, 1994 8. Norton L: Conceptual and practical implications of breast tissue geometry: Toward a more effective, less toxic therapy. Oncologist 10:370-381, 2005 9. Burstein HJ, Parker LM, Keshaviah A, et al: Efficacy of pegfilgrastim and darbepoetin alfa as hematopoietic support for dose-dense every-2-week adjuvant breast cancer chemotherapy. J Clin Oncol 23:8340-8347, 2005 10. Sepkowitz KA: Pneumocystis carinii pneumonia among patients with neoplastic disease. Semin Respir Infect 7:114-121, 1992 11. Worth LJ, Dooley MJ, Seymour JF, et al: An analysis of the utilisation of chemoprophylaxis against Pneumocystis jirovecii pneumonia in patients with malignancy receiving corticosteroid therapy at a cancer hospital. Br J Cancer 92:867-872, 2005 12. Mansharamani NG, Balachandran D, Vernovsky I, et al: Peripheral blood CD4 ⫹ T-lymphocyte counts during Pneumocystis carinii pneumonia in immunocompromised patients without HIV infection. Chest 118:712-720, 2000 13. Citron ML, Berry DA, Cirrincione C, et al: Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 21:1431-1439, 2003
DOI: 10.1200/JCO.2006.08.1083 ■ ■ ■
Authors’ Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. 5331
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