Differential Diagnostic Considerations

Radiology Case Reports

Volume 10, Issue 2, 2015 Chylothorax in a patient with metastatic Kaposi sarcoma: Differential diagnostic considerations

Ryan Alexander, DO; Magda Rizer, DO; William Burke, MD; and Lawrence Ciment, MD

Kaposi sarcoma (KS) is a low-grade mesenchymal tumor involving blood and lymphatic vessels. There are four types, based on clinical presentation: classic, endemic (Africana), iatrogenic (typically, involving renal allograft recipients), and AIDS-associated (epidemic). Kaposi’s sarcoma-associated herpes virus infection has been linked along with other factors to the development of KS. The Kaposi’s sarcoma- associated herpes virus interacts and encodes for numerous molecular proteins that play a role in the pathogenesis of KS, including latency-associated nuclear antigen, viral G protein-coupled receptor, viral FLICE inhibitory protein, and viral IL-6. KS primarily affects the skin and causes disseminated disease in a variety of organs. Involvement of visceral organs other than the lining of the alimentary tract is extremely rare. While the chylous pleural effusions of KS may resemble other pulmonary diseases (including lymphangioma, lymphangectasis, and lymphangioleiomyomatosis) with chylous effusions at thoracic CT, differentiating features may allow for more prompt diagnosis and treatment. The presumptive diagnosis of AIDS-related pulmonary KS is often clinical. A tissue diagnosis is not required to establish the diagnosis of pulmonary KS. There are a variety of causes of chylothorax. The primary ﬁnding is a near- water-attenuating pleural effusion. The secondary ﬁndings of chylothorax can help differentiate the etiology.

Introduction be diagnosed on CT or MRI. The CT finding of chylous Chylothorax is a relatively uncommon cause of pleural effusions is typically a large unilateral effusion of water effusion (1). Lymph in the thoracic duct originates at the attenuation and may demonstrate fat. The MRI findings cisterna chyli and then passes from the abdomen into the may demonstrate high signal intensity on T1WI due to fat mediastinum through the aortic hiatus. It then ascends su- content. periorly in the posterior mediastinum and, at the level of The causes of chylous effusions can be congenital, trau- T5-T6, the thoracic duct crosses to the left side to enter the matic, iatrogenic, malignant, idiopathic, infectious, or in- superior mediastinum (1, 2). Chylous pleural effusions can flammatory (1, 2). Congenital chylothorax occurs more due to congenital malformations than to trauma during deliv- ery (1). Chylothorax is predominantly seen following trauma or cardiothoracic surgery (2, 3). Traumatic injury Citation: Alexander R, Rizer M, Burke W, Ciment L. Chylothorax in a patient with to the thoracic duct is more common with penetrating metastatic Kaposi sarcoma: Differential diagnostic considerations. Radiology Case Reports. (Online) 2015;10(2);1098. trauma than blunt trauma, and is seen with hyperextension injuries (2, 4). Generally, an injury to the lower third of the Copyright: © 2015 The Authors. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs 2.5 License, thoracic duct causes a right chylous effusion, to the upper which permits reproduction and distribution, provided the original work is properly two-thirds of the thoracic duct causes a left chylous effu- cited. Commercial use and derivative works are not permitted. sion, and to the thoracic duct (as it crosses midline) causes Drs. Alexander, Rizer, and Burke are in the Department of Diagnostic Radiology, and Dr. Ciment is in the Department of Pulmonary and Critical Care Medicine, all at Mount bilateral chylous effusions. The thoracic duct can be ob- Sinai Medical Center, Miami Beach, FL. Contact Dr. Alexander at structed from lymphadenopathy (including lymphoma, [email protected]. sarcoidosis, lung cancer, and tuberculosis) (5). We review Competing Interests: The authors have declared that no competing interests exist. the less common causes of chylothorax, including lym- DOI: 10.2484/rcr.v10i2.1098 phangioma, lymphangectasis, and lymphangioleiomyoma-

RCR Radiology Case Reports | radiology.casereports.net 1 2015 | Volume 10 | Issue 2 Chylothorax in a patient with metastatic Kaposi sarcoma: Differential diagnostic considerations tosis (LAM). Familiarity with these entities may lead to a left pleural drain (Fig. 1). Laboratory testing conﬁrmed more prompt recognition and diagnosis. that he was HIV-positive with a CD4 count of 12 cells/μL (427–1625 cells/μL). He was subsequently discharged Case report home in stable condition. As an outpatient, a metastatic evaluation was performed A 21-year-old homosexual male presented with a chief starting with PET/CT (Fig. 2), which demonstrated exten- complaint of abdominal pain and bright red blood per rec- sive lymphadenopathy. His newly diagnosed HIV was tum over the preceding three weeks. He had nausea with- managed with Highly Active Antiretroviral Therapy out vomiting, bloody diarrhea, and 10 bowel movements (HAART), and chemotherapy was initiated for his KS as an per day. He denied any weight loss, fever, chest pain, or outpatient. He then had excision of a right level-ﬁve cervi- shortness of breath. Colonoscopy with rectal biopsies demonstrated KS on pathology. The rectal bleeding was self-limited. He was managed for a left pleural effusion with

Fig 3. Note interval progression of subcutaneous and mesenteric edema over ﬁve months from original admission (A) to readmission (B) due to inﬁltration of the cisterna chylis.

cal lymph node that was positive for metastatic KS. Over the next five months, the patient experienced shortness of breath with upper- and lower-extremity edema responsive Fig 1. Loculated left pleural effusion on original admission. to diuretic therapy (Fig. 3). He was admitted five months later from his original ad- Fig 2. PET/CT. Note mission for exacerbations of these symptoms (Figs. 3, 4). extensive hypermeta- He developed recurrent bilateral bloody chylous pleural bolic lymphadenopathy effusions with progressive shortness of breath and extensive extending from the up- peripheral lymphedema. He was tachycardiac with increas- per cervical regions ing oxygen requirements requiring BiPAP, and eventually throughout all nodal was intubated. stations of the supra- The effusions were resistant to serial thoracentesis and clavicular, axillary, me- pleural drains (Fig. 4). Multiple samples were sent for cytol- diastinal, hilar, retroperi- ogy, which was negative for atypical and malignant cells. toneal, mesenteric, iliac, The location of thoracic duct involvement by KS was to be and inguinal regions. assessed by lymphoscintigraphy before ligation of the duct. There was such extensive inguinal lymphadenopathy that the radiotracer remained at the level of the upper thighs 24 hours post injection (Fig. 5). The thoracic duct at the cisterna chyli was found to be infiltrated with tumor on the chest CT (Fig. 6). The thoracic duct was unable to be safely ligated due to extensive infiltration of the tumor; therefore, bilateral decortications with chest tube placement were performed instead in an attempt to control the chylous effusions. Bronchoalveolar lavage (BAL) demonstrated hemorrhagic secretions with erythema of the bronchioles. An infectious evaluation was negative. The patient expired from cardiopulmonary arrest.

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Fig 4. Recurrent chylous pleural effusions status post-chest-tube placement and talc sclerotherapy. A. Increased right and loculated left pleural effusion on readmission. B. Status post-talc sclerotherapy and removal of right-sided chest tube with worsening loculated right pleural effusion. Note increased loculated and complex left pleural effusion with pleural thickening. Also note consolidative change involving almost the entire left lower lobe, lingual, and left upper lobe.

Fig. 5. Lymphoscintigraphy. An interdermal injection between the web spaces of the toes was performed using Sulfur Colloid bound to the radiotracer Tech-99M. There is migration of Tech-99M ﬁltered Sulfur Colloid radiotracer to the level of the upper thighs within one hour that persists at this level up to 24 hours post injection (arrows). No radiotracer is seen reaching the thorax (arrowheads).

Discussion Involvement of visceral organs other than the lining of KS is a low-grade mesenchymal tumor involving blood the alimentary tract is extremely rare (7, 8). Chylothorax is and lymphatic vessels (6, 7). There are four types based on a rare manifestation of KS involving the thoracic duct (9). clinical presentation: classic, endemic (Africana), iatrogenic KS with chylothorax was initially postulated to develop due (typically renal allograft recipients) and AIDS-associated to metastatic KS to the thoracic duct; more recent ﬁndings (epidemic). Human herpesvirus-8 (HHV8) infection has suggest that this may arise because of in-situ KS in this been linked along with other factors to the development of region (10, 11). KS-related chylothoraces frequently de- KS (6). KS is considered an AIDS-deﬁning illness. velop with concomitant upper-airway KS disease (9).

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proliferation of cytokine-activated endothelial cells, stimu- lating KS growth (13).

Clinical presentation KS primarily affects the skin and causes disseminated disease in a variety of organs. Skin lesions range from several millimeters to several centimeters in size. The lesions are usually not painful or pruritic. Involvement of visceral organs other than the lining of the alimentary tract is extremely rare. Gastrointestinal AIDS-related KS compromise is the most common visceral involvement in disseminated disease, being seen in up to 50% of patients (7). AIDS-related KS can affect any level Fig. 6. Cisterna Chyli infiltrated with tumor. The cisterna of the gastrointestinal tract from the oropharynx to the chyli is identified adjacent to the right side of the abdominal rectum, including the gallbladder (7). The duodenum is the aorta and posterior to the inferior vena cava. The cisterna most frequently affected site (7). chyli appears enlarged and complex in attenuation (arrow). Pulmonary involvement with KS, in the majority of cases, occurs in conjunction with extensive mucocutaneous disease (15). Pulmonary involvement can be the initial Pathophysiology/pathogenesis manifestation (8). Affected patients can present with short- Human herpes virus-8 (also known as Kaposi’s sarcoma- ness of breath, fever, cough, hemoptysis, or chest pain, or associated herpes virus [KSHV]) was discovered by Chang pulmonary involvement may be asymptomatic. When a and Moore and has been linked to the development of KS new diagnosis of KS is suspected in a patient with HIV as well as lymphoproliferative disorders, including primary- infection, the degree of HIV-related immunosuppression is effusion lymphoma and multicentric Castleman disease (12, assessed by measuring the CD4 count and HIV viral load 13). Infection with KSHV is necessary for the development (7). In patients with AIDS-related KS, the CD4 count ap- of KS, although it is not sufficient by itself (13). HIV co- pears to be the most important factor associated with the infection significantly increases the risk of KS (13). KS has development of KS. been found to be more common among persons who are at greater risk for sexually transmitted infections, which led to Imaging manifestations a search for an infectious etiology (14). KS cells have been KS can present with chylothorax. The typical pulmonary screened for infectious agents, including cytomegalovirus, CT findings in AIDS-related KS are the presence of bilat- Epstein Barr virus, human papilloma virus, and myco- eral, ill-defined nodules in a peribronchovascular distribu- plasma; these viral sequences are not uniformly found in tion (flame-shaped lesions representing tumor infiltration KS. involving the bronchovascular bundles), areas of ground- KSHV interacts and encodes for numerous molecular glass opacities (representing edema and blood filling the proteins that play a role in the pathogenesis of KS, includ- airspace) surrounding nodules (the “halo sign”), peribron- ing latency-associated nuclear antigen (LANA), viral G chovascular and interlobular septal thickening (representing protein-coupled receptor, viral FLICE inhibitory protein, edema or tumor infiltration), fissural nodularity, mediasti- and viral IL-6 (12, 13). LANA acts as a transcriptional nal lymphadenopathy, pleural effusions (common), or pleu- regulator binding to tumor-suppressing proteins p53 and ral implants (rare) (6, 7, 16). The nodules correspond to retinoblastoma protein, which promotes the replication of proliferation of neoplastic cells (6). the latent viral episome (12). The viral G protein-coupled receptor leads to proangiogenic signals by the upregulation Diagnosis of hypoxia-inducible factor 1-alpha and the subsequent The presumptive diagnosis of AIDS-related pulmonary expression of vascular endothelial growth factor (VEGF)-A KS is often clinical (16). A tissue diagnosis is not required to and activation of VEGF-receptor-2, which in turn activates establish the diagnosis of pulmonary KS. Bronchoscopy is PI3K-akt and the mammalian target of rapamycin frequently performed to diagnose pulmonary KS with (mTOR) pathway (13). Viral FLICE inhibitory protein is stains, culture, and cytology (which are frequently nega- associated with constitutively activated nuclear factor-κB, tive). The bronchoscopic appearance of endobronchial KS where it then activates a large number of antiapoptotic is considered to be characteristic enough to allow a diagno- genes (12). Viral IL-6 stimulates gp 130 coupled to the sis (6). Parenchymal lesions may occur in the absence of JAK-STAT pathway (13). It is secreted by KSHV-infected tracheobronchial lesions detected by bronchoscopy. Endo- cells, allowing tumor cells to regulate their own growth bronchial KS lesions typically appear violaceous and are through an autocrine pathway (13). A host of other pro- macular or papular, often at airway bifurications (8). Alveo- teins may play a role, including the HIV Tat protein, which lar hemorrhage is frequently diagnosed during BAL (7, 8). has been shown to serve as a growth factor. In animal mod- Endobronchial and transbronchial biopsies have a low di- els, the replication of the HIV virus may enhance the replication of KSHV (13). HIV Tat promotes the migration and

RCR Radiology Case Reports | radiology.casereports.net 4 2015 | Volume 10 | Issue 2 Chylothorax in a patient with metastatic Kaposi sarcoma: Differential diagnostic considerations agnostic yield for KS, with the risk of significant hemor- Conclusion rhage following biopsy (8, 17, 18). KS is a low-grade mesenchymal tumor involving blood In the setting of worsening pulmonary status, the pri- and lymphatic vessels. Kaposi’s sarcoma-associated herpes mary diagnostic role of thoracentesis may be to exclude an virus (KSHV) infection has been linked along with other underlying infection caused by mycobacterium or fungus. factors to the development of KS. KSHV interacts and KS lesions are found on the visceral but not parietal pleura encodes for numerous molecular proteins that play a role in (7). Pleural fluid cytology and biopsies are not helpful in the pathogenesis of KS, including latency-associated nu- diagnosis (19). clear antigen (LANA), viral G protein-coupled receptor, When chylous effusions are identified at thoracic CT, viral FLICE inhibitory protein, and viral IL-6. KS primar- imaging findings allow lymphangioma, lymphangectasis, ily affects the skin and causes disseminated disease in a va- and LAM to be differentiated. Lymphangioma can present riety of organs. Involvement of visceral organs other than with chylothorax. The imaging findings of lymphangioma the lining of the alimentary tract is extremely rare. While are typically a homogeneous, thin-walled, well-defined, the chylous pleural effusions of KS may resemble other low-attenuating cystic mass, though increased attenuation pulmonary diseases with chylous effusions at thoracic CT occurs with high protein content, hemorrhage, or infection. including lymphangioma, lymphangectasis, and LAM, Calcification or contrast enhancement is atypical. These differentiating features may allow for more prompt diagno- lesions insinuate and cause displacement as they spread sis and treatment. The presumptive diagnosis of AIDS- throughout the mediastinum, which also makes complete related pulmonary KS is often clinical. A tissue diagnosis is resection difficult (4). The most common location is the not required to establish the diagnosis of pulmonary KS. superior aspect of the anterior mediastinum. Other rare There are a variety of causes of chylothorax. The primary locations include the pulmonary hila, pericardium, and finding is a near-water-attenuating pleural effusion on tho- intrapulmonary. racic CT. It is the secondary findings of chylothorax that Lymphangectasis can present with chylothorax. The im- can help differentiate the etiology. aging findings of lymphangectasis include bilateral ground- glass opacities, smooth interlobular septal thickening, References marked pleural thickening, and mediastinal soft-tissue infiltration. The imaging findings resemble those of LAM; 1. McGrath EE, Blades Z, Anderson PB. Chylothorax: however, lymphangectasis presents at a younger age with a aetiology, diagnosis and therapeutic options. Resp Med. much more progressive course (2, 4). LAM has dilated lym- 2010;104.1:1-8. [PubMed] phatics like lymphangectasis but also has increased number 2. Soto-Martinez M, Massie J. Chylothorax: Diagnosis of lymphatics. and management in children. Paediatr Respir Rev. LAM can present with chylothorax. The imaging find- 2009;10.4:199-207. [PubMed] ings of LAM include diffuse, thin-walled, uniform lung 3. Kawasaki R, Sugimoto K, Fujii M, et al. Therapeutic cysts (20). LAM is indistinguishable on imaging from tuber- effectiveness of diagnostic lymphangiography for re- ous sclerosis complex. It can cause recurrent fractory postoperative chylothorax and chylous ascites: pneumothorax. Correlation with radiologic findings and preceding medical treatment. Am J Roentgenol. 2013;201.3:659-66. Treatment [PubMed] There is increasing evidence that HAART and an im- 4. Raman S, Pipavath S, Raghu G, Schmidt RA, Godwin proved immune response are associated with complete or JD. Imaging of thoracic lymphatic diseases. Am J partial regression of KS lesions (6, 8, 16). Some studies Roentgenol. 2009;193.6:1504-513. [PubMed] showed that HAART alone can lead to stabilization and 5. Jarman P, Whyte M, Sabroe I, Hughes JM. 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The epidemiologic, pathologic, and Pleural effusions have been managed with repeat thora- clinical features of AIDS-associated pulmonary Ka- centesis in combination with ART and chemotherapy. If posi's sarcoma. Chest. 2000;117:1128-1145. [PubMed] the pleural effusion rapidly reoccurs despite thoracentesis, 9. Pantanowitz L, Dezube BJ. Kaposi sarcoma in unusual an indwelling pleural catheter can be installed, or talc pleu- locations. BMC Cancer. 2008;8:190. [PubMed] rodesis performed. Chylous effusions respond poorly to 10. Konstantinopoulos PA, Dezube BJ, Pantanowitz L. chemical pleurodesis (21). Morphologic and immunophenotypic evidence of in-

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