A 21-Year-Old Male With Dyspnea at Rest, Dry Cough, and Swelling of His Right Anterior Chest CHEST 2010; 137( 3 ):

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1 CHEST Postgraduate Education Corner CHEST IMAGING AND PATHOLOGY FOR CLINICIANS A 21-Year-Old Male With Dyspnea at Rest, Dry Cough, and Swelling of His Right Anterior Chest Andrea G. Adams, MD ; William Tester, MD ; Ghulam Khaleeq, MD ; and Michael Walkenstein, MD, FCCP CHEST 2010; 137( 3 ): year-old, previously healthy, Hispanic male A presented with complaints of resting dyspnea, fatigue, and a nonproductive cough. His shortness of breath was initially exertional but had progressed to resting dyspnea during the past month. The patient stated that he also experienced increasing fatigue. On questioning, he stated that during the past month he had noticed an enlarging area of firmness over his right anterior chest that was mildly tender to palpation. He denied fever, chills, sputum, or hemoptysis. In addition, he had not experienced weight loss, night sweats, or gastrointestinal symptoms. He did describe polyuria and was found to be hyperglycemic when he measured his glucose at home on his mother s glucometer. The patient was a nonsmoker and denied use of alcohol or illicit drugs. He denied any exposure to toxins. He had no drug allergies nor did he use any medications. His family history was significant only for type 2 diabetes. The patient was in the army reserve, having returned from active duty in Iraq 1 year prior to this presentation. Manuscript received January 16, 2009 ; revision accepted June 16, Affiliations: From the Department of Internal Medicine (Dr Adams), the Division of Hematology and Oncology (Dr Tester), and the Division of Pulmonary and Critical Care (Drs Khaleeq and Walkenstein), Albert Einstein Medical Center, Philadelphia, PA. Correspondence to: Ghulam Khaleeq, MD, Associate Department of Pulmonary Disease and Critical Care Medicine, Geisinger Medical Center, Danville, PA 17822; gkhaleeq1@ geisinger.edu. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( site misc reprints.xhtml ). DOI: chest Clinical Findings On physical examination, the patient was anxious and ill appearing. He was tachycardic to 124 bpm and febrile at 38.1 C. BP was ; respiratory rate, 16; and pulse oximetry, 96% on room air. Chest examination revealed a palpable, mildly tender, firm nonmobile mass over the right pectoral area with diffuse borders measuring approximately 8 cm 3 8 cm, with extension into the right axilla. Dullness to percussion was appreciated over the same area. On auscultation, the patient had decreased breath sounds over the right anterior chest. Laboratory findings included a WBC count of 25.0 (75% polymorphonuclear cells) and glucose of 388. Radiologic Findings The chest radiographs ( Fig 1 ) revealed a right upper lobe lesion that was homogenous in density. It had sharply demarcated superior and inferior margins with an obtuse angle supporting an extraparenchymal origin. A CT scan of the chest with IV contrast ( Figs 2, 3 ) demonstrated a large mass occupying much of the right upper chest, causing bowing of the major fissure inferiorly. It compressed the hilar structures medially and extended into the right chest wall with erosion of the right lateral third rib. Small punctate calcifications were noted in the mass adjacent to the rib. No other bony abnormalities were appreciated. There was no evidence of hilar or mediastinal adenopathy. Fiberoptic bronchoscopy examination was done to visualize the airways and to determine if there was a bronchogenic origin or extension of the mass. The bronchoscopy revealed a normal endobronchial examination except for external compression of the right middle lobe bronchus. Subsequently, a transthoracic needle biopsy of the mass was performed. CHEST / 137 / 3 / MARCH,

2 Figure 1. A posteroanterior and lateral view of the chest revealing a large opacity within the right hemithorax. PA 5 posteroanterior. Pathologic Findings Hematoxylin and eosin-stained sections revealed abundant abnormal cellular tissue consisting of fragments of small blue cells embedded in fibrous stroma ( Fig 4 ). The blue cells were arranged in sheets and demonstrated mild nuclear irregularity. Fluorescence in situ hybridization revealed a translocation t(11;22) (q24;q12). Immunohistochemical staining revealed vimentin and CD99 MIC2 positivity ( Fig 5 ). Desmin, smooth muscle actin, and leukocyte common antigen (LCA) were negative. Figure 2. Coronal view showing large heterogeneous density in the right upper chest, bowing the major fissure inferiorly and compressing the hilar structures medially. Figure 3. A transverse cut from a CT scan of the chest showing mass in its largest dimensions. 730 Postgraduate Education Corner

3 Figure 4. Hematoxylin and eosin stain of biopsy specimen showing small blue cells arranged in sheets (original magnification 315). Figure 5. CD99 staining of biopsy tissue (original magnification 340). What is the diagnosis? CHEST / 137 / 3 / MARCH,

4 Diagnosis: Primitive neuroectodermal tumor Ewing sarcoma family of tumors Discussion The differential diagnosis for a chest wall mass with bony invasion includes infections and neoplasms. Bacterial infections, such as actinomycosis and nocardiosis, are the most likely infectious causes. Other rare possibilities include a cold tuberculous chest wall abscess. 1 The most common neoplastic origin based on the patient s imaging would be a bronchogenic carcinoma, but given his age and nonsmoking status other entities must be entertained. Lymphomas; primary intrathoracic sarcomas, such as angiosarcoma, leiomyosarcoma, and rhabdomyosarcoma; and chest wall sarcomas, such as primitive neuroectodermal tumor (PNET), chondrosarcoma, malignant fibrous histiocytomas, synovial sarcomas, fibrosarcomas, and osteosarcomas, must be included in the differential. Solitary fibrous tumors of the pleura can also present as a pleural-based mass that could measure up to 24 cm in diameter. 2 It enhances on CT scanning after intravenous contrast administration. It can have cystic components and a pedicle is noted in approximately 40% of cases that results in marked tumor mobility. 3 Immunohistochemical staining will aid in differentiating PNET Ewing sarcoma family of tumors (ESFT) from other small round cell tumors and should include CD99 MIC2, vimentin, desmin, LCA, neuronspecific enolase, epithelial membrane antigen, and cytokeratins. 4 CD99 MIC2 is expressed by 90% of ESFTs 4 but is not specific because it is also expressed in many other tumors and normal tissues. 5 Vimentin is a sarcoma tumor marker and identifies mesenchyme. Embryonal rhabdomyosarcomas stains positive desmin, myoglobin, and muscle-specific actin. 4 LCA positivity along with other T- and B-cell markers are found in lymphomas. Neuron-specific enolase is positive in neuroblastomas along with elevated urine catecholamines. Epithelial membrane antigen and LCA positivity identify small round cell anaplastic tumors of the thyroid. 6 Other neuroendocrine markers that may aid in the diagnosis include: pro-gastrin-releasing peptide positivity for small cell lung cancer and chromogranin-a positivity for carcinoid. 4, 5 Thyroid transcription factor-1 is considered as a reliable marker in distinguishing primary adenocarcinomas of the lung from extrathoracic origins. 7 Cytogenetic evaluation demonstrating the t(11;22) (q24;q12) translocation that we described earlier is diagnostic for Ewing sarcoma and is present in. 85% of cases. 4 In 1979, Askin et al 8 described a malignant, small cell tumor of the thoracopulmonary region, which today belongs to the spectrum of ESFT. The ESFT PNET Figure 6. A posteroanterior view of the chest after neoadjuvant chemotherapy. family also includes several other related clinicopathologic neoplastic entities, such as adult neuroblastoma, paravertebral small cell tumor, atypical Ewing sarcoma, PNET of bone, extraosseous Ewing sarcoma, and the malignant small cell tumor of the thoracopulmonary region known as Askin tumor. 9 These tumors are poorly differentiated, small, round cell tumors. It is Figure 7. CT scan showing marked shrinking of the mass with neoadjuvant chemotherapy. 732 Postgraduate Education Corner

5 believed that the ESFT is derived from pluripotent neural crest cells that have features of parasympathetic postganglionic cholinergic neurons. 10 ESFTs affect primarily white and Hispanic young people for reasons that are unknown, and they occur most frequently in the second decade of life accounting for 2% to 4% of childhood and adolescent malignancies. ESFTs are morphologically heterogeneous but genetically distinct in that they all involve chromosomal translocations and functional fusion of the Ewing sarcoma gene on chromosome 22 to one of the many structurally related transcription factor genes. The most common mutation is a reciprocal translocation of the long arms of chromosome 11 and 22, t(11:22), which creates a chimeric gene product of unknown function with components from the fli-1 gene on chromosome 11 and the Ewing sarcoma gene on chromosome The resulting proteins are believed to contribute to tumor biology by altering cellular proliferation and differentiation. The clinical features that may suggest metastasis include fever, anemia, and elevated lactate dehydrogenase levels. Although advancing age (. 10 y) and increasing tumor volume (. 100 ml) are negative prognostic factors, detectable metastasis at diagnosis is the most important negative prognostic factor in ESFT. 11,12 Nearly all patients have micrometastases at diagnosis, evidenced by local therapy alone providing a 10% cure rate. 13 Metastases most commonly occur in the lungs and bone. 4 Treatment consists of systemic chemotherapy and local control with surgery, radiation therapy, or both. As many as 50% of patients with localized disease relapse within 3 years. For patients without evidence of metastatic disease, 5-year survival rates approach 50%. 14 Our patient s bone marrow biopsy did not reveal metastasis, nor did imaging reveal overt metastatic disease. There are emerging data to prove that fluorodeoxyglucose PET scan is a more sensitive indicator than bone scan; however, it does not visualize the bones below the femur. 15 Oncology was consulted, and the patient was started on a neoadjuvant chemotherapy regimen of doxorubicin, vincristine, and cyclophosphamide, alternating with courses of iphosphamide and etoposide. Our patient initially presented with uncontrolled diabetes but after receiving chemotherapy his diabetes was better controlled. In a recent article on long-term survivors of pediatric sarcoma they were noticed to have an increased prevalence of metabolic syndrome that includes a cluster of central obesity, dyslipidemia, hyperglycemia, and hypertension. 16 Follow-up chest radiography and CT scanning of the chest after the second cycle of chemotherapy showed marked improvement of the bulky lesion ( Figs 6, 7 ). The patient subsequently underwent a right posterolateral thoracotomy with partial right upper lobe resection, resection of the lateral portions of his third and fourth ribs, and chest reconstruction. Pathology revealed clean margins without evidence of active tumor in the surgical resection. The patient remains disease-free 3 years later. In addition, the hyperglycemia resolved with treatment of the tumor. Conclusion This case report illustrates the chemosensitivity of Askin tumors and underscores the importance of pathologic evaluation of chest wall masses at presentation for prompt initiation of therapy. Prompt diagnosis and treatment can result in cure. 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. References 1. Morris BS, Maheshwari M, Chalwa A. Chest wall tuberculosis: a review of CT appearances. Br J Radiol ;77(917): Orki A, Kosar A, Akin O, Haciibrahimoglu G, Arman SB. Solitary fibrous tumor of the pleura. Thorac Cardiovasc Surg ;56(5): Desser TS, Stark P. Pictorial essay: solitary fibrous tumor of the pleura. J Thorac Imaging ;13(1): Gautam U, Srinivasan R, Rajwanshi A, Bansal D, Marwaha RK. Comparative evaluation of flow-cytometric immunophenotyping and immunocytochemistry in the categorization of malignant small round cell tumors in fine-needle aspiration cytologic specimens. Cancer ;114(6): de Alava E, Gerald WL. Molecular biology of the Ewing s sarcoma primitive neuroectodermal tumor family. J Clin Oncol ;18(1): Burt AD, Kerr DJ, Brown IL, Boyle P. Lymphoid and epithelial markers in small cell anaplastic thyroid tumours. J Clin Pathol ;38(8): Compérat E, Zhang F, Perrotin C, et al. Variable sensitivity and specificity of TTF-1 antibodies in lung metastatic adenocarcinoma of colorectal origin. Mod Pathol ;18(10): Askin FB, Rosai J, Sibley RK, Dehner LP, McAlister WH. Malignant small cell tumor of the thoracopulmonary region in childhood: a distinctive clinicopathologic entity of uncertain histogenesis. Cancer ;43(6): Grier HE. The Ewing family of tumors. Ewing s sarcoma and primitive neuroectodermal tumors. Pediatr Clin North Am ;44(4): Scurr M, Judson I. How to treat the Ewing s family of sarcomas in adult patients. Oncologist ;11(1): Cotterill SJ, Ahrens S, Paulussen M, et al. Prognostic factors in Ewing s tumor of bone: analysis of 975 patients from the European Intergroup Cooperative Ewing s Sarcoma Study Group. J Clin Oncol ;18(17): Craft A, Cotterill S, Malcolm A, et al. Ifosfamide-containing chemotherapy in Ewing s sarcoma: The Second United Kingdom Children s Cancer Study Group and the Medical Research CHEST / 137 / 3 / MARCH,

6 Council Ewing s Tumor Study. J Clin Oncol ;16 (11 ): Terrier P, Llombart-Bosch A, Contesso G. Small round blue cell tumors in bone: prognostic factors correlated to Ewing s sarcoma and neuroectodermal tumors. Semin Diagn Pathol ;13 (3 ): Grier HE, Krailo MD, Tarbell NJ, et al. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing s sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med ;348 (8 ): Györke T, Zajic T, Lange A, et al. Impact of FDG PET for staging of Ewing sarcomas and primitive neuroectodermal tumours. Nucl Med Commun ;27 (1 ): Hoffman KE, Derdak J, Bernstein D, et al. Metabolic syndrome traits in long-term survivors of pediatric sarcoma. Pediatr Blood Cancer ;50 (2 ): Postgraduate Education Corner