CHEST. Postgraduate Education Corner. A 19-Year-Old Woman With Progressive Dyspnea and Multiple Pulmonary Nodules

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1 CHEST Postgraduate Education Corner PULMONARY AND CRITICAL CARE PEARLS A 19-Year-Old Woman With Progressive Dyspnea and Multiple Pulmonary Nodules Don Hayes Jr, MD, FCCP ; Melissa V. Kesler, MD ; Sean C. Skinner, MD ; and Anil K. Attili, MD CHEST 2011; 140( 1 ): year-old woman with a history of asthma was A transferred from a community hospital for cough and progressive dyspnea over the past month. There was no history of fever, chills, night sweats, weight loss, or headache. Her medical history included allergic rhinitis and asthma, which was diagnosed 10 years earlier. Medications included intermittent need for budesonide/formoterol, albuterol, and fexofenadine. Social history included that she attends high school, lives with her parents, and has no previous alcohol or tobacco use. There was a reported history of thyroid cancer in one family member. Initially, the patient restarted treatment with budesonide/formoterol and increased use of albuterol by metered dose inhaler with no improvement during the first week of onset of symptoms, so she presented to her local primary care physician and started treatment with azithromycin and a 5-day course of prednisone for suspected asthma exacerbation. A chest radiograph was not obtained at that time. Still, there was no improvement in the dyspnea, so she presented to a local ED. At that time, several pulmonary nodules were apparent on a radiograph and an immediate CT chest scan showed multiple pulmonary nodules ranging in size from a few millimeters to 2 cm ( Fig 1 ). The nodules were noncalcified, and there was no Manuscript received December 1, 2010 ; revision accepted December 20, Affiliations: From the Departments of Pediatrics (Dr Hayes), Internal Medicine (Dr Hayes), Surgery (Drs Hayes and Skinner), Pathology (Dr Kesler), and Radiology (Dr Attili), University of Kentucky Medical Center, Lexington, KY. Correspondence to: Don Hayes Jr, MD, FCCP, Departments of Pediatrics, Internal Medicine, and Surgery, University of Kentucky College of Medicine, C424 University of Kentucky Medical Center, 800 Rose St, Lexington, KY 40536; don.hayes@uky.edu. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http :// / site /misc /reprints.xhtml ). DOI: /chest mediastinal lymph node enlargement. Upon local hospitalization, the patient received a diagnosis of histoplasmosis and began itraconazole therapy. She underwent bronchoscopy to obtain BAL for cultures, which ultimately did not culture any pathogens. Because of persistent dyspnea, the patient was eventually transferred to our institution for further care. Physical Examination On hospital admission, the patient was in no distress while breathing room air. Vital signs were as follows: temperature, 37 C; BP, 105/72 mm Hg; heart rate, 78 beats/min; respiratory rate, 18 breaths/min; and oxygen saturation, 95% on room air. A head and neck examination revealed boggy lower nasal turbinates but was otherwise normal. A heart examination demonstrated normal heart sounds without murmurs or gallops. The lungs were clear to auscultation bilaterally. On abdominal examination, there was a palpable mass in the right-side upper quadrant. The patient had no clubbing, thyromegaly, or signs of lymphadenopathy. Figure 1. CT scan of the chest demonstrating multiple pulmonary nodules ranging in size from a few millimeters to 2 cm. CHEST / 140 / 1 / JULY,

2 Figure 4. Fluorodeoxyglucose-PET scan of the lower lungs demonstrating intense uptake in the larger lung nodule in the left-side lower lobe in proximity of the heart. Figure 2. CT scan of the abdomen with coronal reformation demonstrating a large right-side lower-quadrant soft-tissue mass involving the right-side iliacus muscle and extending into the upper thigh. abdomen with coronal reformation showed a large, right-side lower-quadrant soft-tissue mass involving the right iliacus muscle and extending into the upper thigh ( Fig 2 ). PET scan with fluorodeoxyglucose was performed through the pelvis and lower lungs and showed intense uptake in the right-side lowerquadrant mass ( Fig 3 ) and in the larger lung nodule in the left-side lower-lobe adjacent to the heart ( Fig 4 ). Subsequently, the patient was taken to the operating room for an open biopsy of the mass (Figs 5, 6 ). Laboratory and Radiographic Findings Blood tests results included a WBC count of 6,100/ m L and a hemoglobin level of 11.6 g/dl. Renal function, electrolyte panel, liver panel, and coagulation times were unremarkable. Westergren sedimentation rate was elevated at 66 mm/h. Spirometry revealed an FVC of 3.96 L (110% predicted) and FEV 1 of 3.11 L (97% predicted). CT imaging of the Figure 3. Fluorodeoxyglucose-PET scan of the pelvis demonstrating intense uptake in the right-side lower-quadrant mass. Figure 5. Malignant cells in an organoid or pseudoalveolar pattern with eosinophilic granular cytoplasm, vesicular nuclei, and prominent nucleoli (hematoxylin-eosin stain, original magnification 3 200). 254 Postgraduate Education Corner

3 Figure 6. Diastase-resistant intracytoplasmic crystals that are periodic acid-schiff positive (periodic acid-schiff stain with diastase, original magnification 3 1,000). What is the diagnosis? CHEST / 140 / 1 / JULY,

4 Diagnosis: Alveolar soft part sarcoma Discussion Alveolar soft part sarcoma (ASPS) is a rare softtissue tumor that is uniformly malignant and occurs principally in adolescents and young adults, with a female predilection. The estimated frequency of ASPS is 0.5% to 1% of all soft-tissue sarcomas. Because it is a tumor that typically grows slowly and causes few to no local symptoms, the first clinical manifestation of disease in ASPS is frequently metastases to the lung or brain. Local relapse after complete resection is uncommon, but metastases can occur decades after resection of the primary tumor, despite the absence of local recurrence. Because of the risk of late metastasis, complete microscopic excision is essential, especially when localized. Therefore, this tumor requires an early and accurate diagnosis for optimal treatment. There is a distinct difference in the anatomic areas infected by tumor in ASPS in adults vs children. In adults, ASPS predominantly occurs in the lower extremities with a variety of other reported locations that include the mediastinum, breast, bone, GI tract, female genital tract, and urinary bladder. In infants and children, the tumor often occurs in the head and neck region, most frequently around the orbit and tongue. The histologic differential diagnoses of ASPS include any tumor composed of large cells with eosinophilic/clear cytoplasm in an organoid or pseudoalveolar pattern, which would include, but is not limited to, adrenal cortical carcinomas, hepatocellular carcinoma, malignant melanoma, and renal clear cell carcinoma. Other considerations are paraganglioma and schwannoma. Expression of immunohistochemical markers is variable in ASPS and often not useful in achieving a diagnosis, but they may help to exclude other tumors. The diagnosis depends on morphologic characteristics of the tumor with periodic acid-schiff (PAS) stain with diastase being the most helpful stain. Coarse PAS-positive diastaseresistant granules with occasional rod-shaped or crystalline structures are the histologic hallmark of the tumor. ASPS has a characteristic cytogenetic abnormality [t(x;17)(p11;q25)], and the diagnosis can be confirmed either by cytogenetics or by molecular testing to identify the fusion product created as a result of the translocation. The radiographic differential diagnosis for multiple noncalcified pulmonary nodules includes disseminated fungal infections, TB, nodular sarcoidosis, metastases, and nodules due to collagen vascular diseases, such as rheumatoid nodules and Wegener granulomatosis. Among the endemic fungal infections in immunocompetent patients, acute disseminated histoplasmosis can cause multiple pulmonary nodules that generally are smaller in size in the range of 3 mm and are usually accompanied by thoracic lymph node enlargement. Other radiographic patterns in disseminated histoplasmosis include pneumonic consolidation and diffuse reticulonodular patterns. A similar radiographic pattern of profuse small nodules can be produced by military TB. Although nodules due to collagen vascular disorders such as rheumatoid nodules and Wegener disease may be larger in size, cavitation is frequent. Treatment of ASPS primarily is surgical, with minor roles for chemotherapy and radiotherapy. Prognosis is much better in children. Because ASPS is so rare, the majority of studies are case reports or small series. In a recently published large series of 33 patients with ASPS, local resection was achieved in 27. Adjuvant radiotherapy was delivered in 12 cases, and six of these patients also received chemotherapy. Older studies involving two large series reported survival rates for patients without evidence of metastases at the time of diagnosis as 60% and 87% at 5 years. More recently, the overall survival was reported as 68.7% at 5 years and 53.4% at 10 years. Clinical Course The histologic examination with hematoxylin-eosin stain at magnification demonstrated nests of malignant cells in an organoid or pseudoalveolar pattern ( Fig 5 ). PAS staining at 31,000 magnification showed rare PAS-positive diastase-resistant intracytoplasmic crystals ( Fig 6 ) that are considered diagnostic. Reverse transcriptase polymerase chain reaction on formalin-fixed paraffin-embedded tissue identified the fusion product of the t(x;17)(p11;q25), which is characteristic of ASPS. The patient was given a diagnosis of ASPS and received induction chemotherapy at our institution. She was referred to a larger oncology program and enrolled into a study protocol. The patient remains alive, but her disease has continued to progress, which is consistent with the medical literature that the prognosis of this tumor is poor if not diagnosed early and completely resected. Clinical Pearls 1. ASPS should be considered in the differential diagnosis of a child or young adult presenting with multiple pulmonary nodules. 2. ASPS is a very rare, malignant tumor that commonly presents with metastasis, which often involves the lung and brain. 3. In the histologic evaluation of ASPS, PAS and immunohistochemical stains are useful in establishing 256 Postgraduate Education Corner

5 the diagnosis or, more importantly, in helping to exclude other disorders in the differential diagnosis. Cytogenetic analysis or molecular testing can confirm the diagnosis of ASPS. 4. Tumors that are large in size at the time of diagnosis are very suggestive of indolent disease, which allows more time for systemic spread and partially explains why there is such a high rate of metastasis in all reported series. 5. Clinicians should be aware of the risk for recurrence or distant metastases of this aggressive tumor despite complete surgical resection and chemotherapy and radiation therapy when indicated. 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. Other contributions: The manuscript was prepared at the University of Kentucky Division of Pulmonary and Critical Care Medicine, Lexington, KY. This article did not require institutional review board approval. Suggested Readings Christopherson WM, Foote FW Jr, Stewart FW. Alveolar softpart sarcomas; structurally characteristic tumors of uncertain histogenesis. Cancer ;5(1): McGlamory JC, Harris JO. Alveolar soft-part sarcoma. Report of a case presenting as asymptomatic pulmonary nodules. Chest ;62(6): Evans HL. Alveolar soft-part sarcoma. A study of 13 typical examples and one with a histologically atypical component. Cancer ;55(4): Lieberman PH, Brennan MF, Kimmel M, Erlandson RA, Garin- Chesa P, Flehinger BY. Alveolar soft-part sarcoma. A clinicopathologic study of half a century. Cancer ;63(1):1-13. Gurney JW, Conces DJ. Pulmonary histoplasmosis. Radiology ;199(2): Ordóñez NG. Alveolar soft part sarcoma: a review and update. Adv Anat Pathol ;6(3): Portera CA Jr, Ho V, Patel SR, et al. Alveolar soft part sarcoma: clinical course and patterns of metastasis in 70 patients treated at a single institution. Cancer ;91(3): Daigeler A, Kuhnen C, Hauser J, et al. Alveolar soft part sarcoma: clinicopathological findings in a series of 11 cases. World J Surg Oncol ;6:71. Pennacchioli E, Fiore M, Collini P, et al. Alveolar soft part sarcoma: clinical presentation, treatment, and outcome in a series of 33 patients at a single institution. Ann Surg Oncol ; 17 (12): CHEST / 140 / 1 / JULY,