CHEST. Postgraduate Education Corner. A 45-Year-Old Man With Skin Lesions and Pleural Effusion
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1 CHEST Postgraduate Education Corner A 45-Year-Old Man With Skin Lesions and Pleural Effusion PULMONARY AND CRITICAL CARE PEARLS Viswanath Vasudevan, MD, FCCP ; Sasikanth Nallagatla, MD ; Philip Xiao, MD ; Farhad Arjomand, MD, FCCP ; and Ihsan Khan, MD CHEST 2010; 138( 6 ): year-old Hispanic man with no significant A medical history presented with 2 weeks of progressive dyspnea, left-sided chest pain, and nonproductive cough. He denied fever, night sweats, hemoptysis, or weight loss. The patient had no significant occupational or environmental exposures, including no known exposure to asbestos, and denied smoking or illicit drug use. He denied IV drug use, multiple sexual partners, and homosexuality. Physical Examination The patient was in mild respiratory distress, with a BP of mm Hg, a heart rate of 98 beats min, tem perature of 36.8 C, and respiratory rate of 22 breaths min. Finger pulse oxygen saturation was 97% while breathing oxygen through a nasal cannula at 2 L min. He had discrete, firm, nonmatted cervical, axillary, and inguinal palpable lymphadenopathy and oral thrush. Chest examination revealed dullness to percussion and decreased breath sounds on the left side. Abdominal examination revealed multiple skin lesions measuring 1.5 cm in diameter; erythematous; and raised, firm, and well-demarcated plaques, some with darker centers ( Fig 1 ). Other systems were normal. Laboratory and Radiologic Findings Blood tests showed a hemoglobin concentration of 12.6 g dl; lactate dehydrogenase, 514 U L; total protein, 5.4 g dl; and albumin, 3.1 g dl. Renal panel, electrolyte levels, coagulation panel, and thyroidstimulating hormone levels were unremarkable. A plain chest radiograph ( Fig 2 ) and chest CT scan ( Fig 3 ) revealed massive left-sided effusion with contralateral shift of the mediastinum. Pleural thickening, pleural mass, or mediastinal adenopathy was absent. Therapeutic, left-sided thoracentesis revealed straw-colored nonhemorrhagic exudative effusion with a total protein concentration of 3.8 g L and lactate dehydrogenase concentration of 277 U L. Pleural fluid ph was 7.27; WBC count, 4,910 cells ml; RBC count, Manuscript received March 30, 2010 ; revision accepted June 1, Affiliations: From the Pulmonary Disease Department, Brooklyn Hospital Center, Brooklyn, NY. Correspondence to: Viswanath Vasudevan, MD, FCCP, Pulmonary Disease Department, Brooklyn Hospital Center, 121 DeKalb Ave, Brooklyn, NY 11201; vpv9002@nyp.org. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( http : site misc reprints.xhtml ). DOI: /chest Figure 1. Skin lesion on abdomen Postgraduate Education Corner
2 Figure 2. Posteroanterior chest radiograph showing massive left pleural effusion with mediastinal shift to the right. 19,690 cells ml; neutrophils, 5%; lymphocytes, 88%; monocytes, 7%; and mesothelial cells, moderate. Pleural fluid cytology was negative for malignant cells. The results of Gram stain, acid-fast bacilli, and cultures were negative. The results of HIV and rapid plasmin reagin serology were negative. Paraphenylenediamine was nonreactive. What is the diagnosis, and what investigation was performed? Figure 3. CT scan of the chest showing extremely large left pleural effusion occupying the entire left hemithorax with complete collapse of the left-side lung. CHEST / 138 / 6 / DECEMBER,
3 Diagnosis and Investigation: Cutaneous T-cell lymphoma initially confirmed by skin biopsy specimen and subsequently by pleural fluid flow cytometry Discussion Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of lymphoproliferative disorders characterized by localization of malignant T lymphocytes in the skin at presentation. There are two classic subsets of this disease. Mycosis fungoides (MF) is the more common form of CTCL in which the skin is affected variably by flat patches, thin plaques, or tumors pathologically characterized by an epidermotropic skin infiltrate of atypical CD4 1 helper T-cell clones. Sézary syndrome (SS) is characterized by erythroderma and leukemia when malignant (Sézary) cells are present in the peripheral blood. The causes of MF and SS are unclear. Current hypotheses include genetic predisposition and environmental and occupational exposure to solvents and chemicals. The incidence of MF is approximately six cases per million per year, accounting for about 4% of all cases of non-hodgkin s lymphoma. According to SEER (Surveillance, Epidemiology, and End Results) data, the incidence of MF has been increasing since The peak age at presentation is 55 to 60 years, with the disease affecting twice as many men as women and being more common in blacks. Although MF is a disease mainly of older patients, it can be seen in patients aged, 35 years with similar clinical findings and course. The incidence of SS is significantly less than MF ( 0.3 cases per million per year). The most common clinical feature of MF is pruritic skin lesions that are heterogeneous and include patches, plaques, tumors, and generalized erythroderma, which is a late manifestation. Differential diagnoses include benign skin conditions, such as psoriasis, eczema, parap soriasis, photodermatitis, or drug reactions. Extracutaneous manifestations are most common among patients with tumorous or generalized erythrodermatous involvement. Regional lymph node involvement occurs in about 30% of patients with MF. Lungs, spleen, and GI tract may also be involved. Bone marrow involve ment is rare. Autopsy studies and a large case series have shown that involvement of any organ, including the CNS, can occur in the advanced stages of the disease. An algorithm for diagnosing and staging early MF that is based on clinical, histopathologic, molecular, and immunopathologic criteria has been proposed by the International Society for Cutaneous Lymphoma and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer. The percentages of patients presenting with the various T-stages in large series are as follows: T1, limited patch plaque (, 10% of the skin surface involved), 30%; T2, generalized patch plaque (. 10% of the skin surface involved), 35%; T3, tumorous skin involvement, 20%; and T4, erythroderma, 15%. Patients with local or generalized patch plaque disease without evidence of extracutaneous involvement have a median survival rate of. 11 years. The median survival of extracutaneous nodal and visceral involvement is 14 and 11 months, respectively. Preferred treatment of limited-stage disease is the combination of localized radiation (ie, electron beam therapy or x-ray therapy) to the tumors plus skindirected therapy for concurrent patch plaque disease. Electron beam therapy is preferred to x-ray therapy for most patients. Stage IV disease principally is treated with systemic therapy, although most regimens result in temporary palliative control only. Chemotherapy can be used alone or in combination with other skindirected therapy (eg, radiation) or biologic response modifiers (eg, interferon- a ). With combination chemotherapy regimens, overall complete and partial response rates can reach 80% to 100%. However, in most cases, the median duration of response is, 1 year and in many patients less than a few months. In addition, patients with stage IV disease are potential candidates for allogeneic hematopoietic cell transplantation. The lungs are among the most common sites of visceral involvement, although lung involvement usually is diagnosed at autopsy. The University of Texas M. D. Anderson Cancer Center analyzed 710 patients with confirmed CTCL between 1996 and The incidence of lung involvement by CTCL was, 1% (6 710) of all patients with CTCL. Thoracic CT imaging revealed either solitary or multiple progressing lung nodules. Pneumonia as a complication of CTCL or chemotherapy-induced immunosuppression was noted in 27 patients. These findings were associated with high mortality. Several other case reports have described other findings, including peribronchovascular nodules with surrounding ground-glass opacities, multiple bilateral parenchymal nodular densities, patchy areas of consolidation, bilateral pulmonary infiltrates, interstitial infiltrations with or without hilar adenopathy, and pleural effusion without underling parenchymal disease. Radiologic and pathologic demonstration of disease progression beyond the primary site is important because it has been suggested that patients with such involvement may respond to appropriate antineoplastic treatment by chemotherapy or radiation therapy to the lung. The thoracic duct obstruction and impaired lymphatic drainage secondary to hilar and mediastinal 1514 Postgraduate Education Corner
4 lymph node involvement appear to be the primary mechanism for pathogenesis of pleural effusion in Hodgkin s disease. Direct pleural infiltration is the predominant cause in non-hodgkin s lymphoma. Exudative lymphocytic pleural effusion can present as a diagnostic dilemma. Up to 15% to 20% of cases remain undiagnosed following the initial pleural fluid analysis. If lymphoma is a strong clinical consideration in the differential diagnosis, flow cytometry of the pleural fluid should be obtained. Additional studies on pleural fluid, such as immunocytochemistry, morphometry, and cytogenetics and molecular genetics (polymerase chain reaction, in situ hybridization, and Southern blotting), will help to confirm the diagnosis of lymphoma and will obviate the need for more invasive surgical diagnostic procedures like video-assisted thoracoscopic pleural biopsy or mediastinoscopy and biopsy of enlarged lymph nodes. Clinical Course In our case, biopsy specimens of skin lesions revealed small-to-intermediate-sized malignant lymphoid infiltrate in the dermis and subcutis ( Fig 4A ). Tumor cells were positive for CD3, CD4, CD5 ( Fig 4B ) but negative for CD20, myeloperoxidase, CD68, and CD30 ( Fig 4C ) consistent with T-cell lymphoma. The patient subsequently developed right-sided pleural effusion during the course of stay, and the repeat thoracentesis revealed exudative effusion with lymphocyte predominance. At this time, pleural fluid flow cytometry was positive for lymphocyte markers for lymphoma CD3, CD4, and CD5, which illustrated the dissemination of CTCL to the lung. Our patient received one cycle of chemotherapy with CHOP (cyclophosphamide, hydroxydaunorubicin, Oncovin [vincristine], and prednisone) regimen and discharged for follow-up. The patient died of respiratory failure after 3 months. Clinical Pearls 1. In patients who present with nondiagnostic exudative lymphocytic-predominant pleural effusion, high lactate dehydrogenase, and cutaneous lesions and peripheral lymphadenopathy, CTCL should be considered. 2. The diagnosis of CTCL should be suspected in patients who present with chronic, nonspecific dermatitis, poikilodermatous skin findings, or generalized erythroderma, and an early skin biopsy is recommended. 3. In patients with unexplained exudative pleural effusions with lymphocyte predominance and skin lesions, consider pleural fluid flow cytometry for lymphocyte markers. Figure 4. Skin biopsy specimen. A, Skin biopsy specimen of small-to-intermediate-sized malignant lymphoid infiltrate in the dermis and subcutaneous tissue (hemotoxylin and eosin stain, original magnification 3 10). B, Tumor cells positive for CD3, CD4, and CD5 (immunohistochemic stain, original magnification 3 20). C, Lymphocytes are positive for CD8 and CD7; CD20, myeloperoxidase, CD68, and CD30 are negative (immunohistochemic stain, original magnification 3 20). CHEST / 138 / 6 / DECEMBER,
5 Acknowledgments Financial nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies organizations whose products or services may be discussed in this article. Suggested Readings Wolfe JD, Trevor ED, Kjeldsberg CR. Pulmonary manifestations of mycosis fungoides. Cancer ;46(12): Foster GH, Eichenhorn MS, Van Slyck EJ. The Sézary syndrome with rapid pulmonary dissemination. Cancer ; 56 ( 5 ): Rubin DL, Blank N. Rapid pulmonary dissemination in mycosis fungoides simulating pneumonia. A case report and review of the literature. Cancer ;56(3): Stokar LM, Vonderheid EC, Abell E, Diamond LW, Rosen SE, Goldwein MI. Clinical manifestations of intrathoracic cutaneous T-cell lymphoma. Cancer ;56(11): Miller KS, Sahn SA. Mycosis fungoides presenting as ARDS and diagnosed by bronchoalveolar lavage. Radiographic and pathologic pulmonary manifestations. Chest ;89(2): Patel DJ, Griem ML, Vijayakumar S, Griem SF. Treatment of pulmonary mycosis fungoides with whole-lung radiation therapy. J Surg Oncol ;38(2): Kitching PA, Gibbs AR. Pulmonary involvement by mycosis fungoides. A case showing angiocentric lesions and granulomas. Pathol Res Pract ;189 (5 ): Bunn PA Jr, Hoffman SJ, Norris D, Golitz LE, Aeling JL. Systemic therapy of cutaneous T-cell lymphomas (mycosis fungoides and the Sézary syndrome). Ann Intern Med ;121 (8 ): Rosen ST, Foss FM. Chemotherapy for mycosis fungoides and the Sézary syndrome. Hematol Oncol Clin North Am ; 9 (5 ): Gómez-De La Fuente E, Ortiz PL, Vanaclocha F, Rodriguez- Peralto JL, Iglesias L. Aggressive granulomatous mycosis fungoides with clinical pulmonary and thyroid involvement. Br J Dermatol ;142 (5 ): Ueda T, Hosoki N, Isobe K, et al. Diffuse pulmonary involvement by mycosis fungoides: high-resolution computed tomography and pathologic findings. J Thorac Imaging ;17 (2 ): Duvic M, Apisarnthanarax N, Cohen DS, Smith TL, Ha CS, Kurzrock R. Analysis of long-term outcomes of combined modality therapy for cutaneous T-cell lymphoma. J Am Acad Dermatol ;49 (1 ): Das DK. Serous effusions in malignant lymphomas: a review. Diagn Cytopathol ;34 (5 ): Baser S, Onn A, Lin E, Morice RC, Duvic M. Pulmonary manifestations in patients with cutaneous T-cell lymphomas. Cancer ;109 (8 ): Postgraduate Education Corner
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