Advanced therapy in thoracic surgery - part 8 pps

Lung Retransplantation / 385 15 Novick RJ, Kaye MP, Patterson GA, et al Redo lung transplantation: a North American–European experience J Heart Lung Transplant 1993;12(Pt 1):5–15; discussion 15–6 16 Struber M, Wilhelmi M, Harringer W, et al Flush perfusion with low potassium dextran solution improves early graft function in clinical lung transplantation Eur J Cardiothorac Surg 2001;19:190–4 17 Fischer S, Matte-Martyn A, De Perrot M, et al Lowpotassium dextran preservation solution improves lung function after human lung transplantation J Thorac Cardiovasc Surg 2001;121:594–6 18 Pierre AF, Sekine Y, Hutcheon MA, et al Marginal donor lungs: a reassessment J Thorac Cardiovasc Surg 2002;123:421–7; discussion 427–8 CHAPTER 31 LUNG XENOTRANSPLANTATION: LESSONS LEARNED AND FUTURE PERSPECTIVES CARSTEN SCHRÖDER, MD PAOLO MACCHIARINI, MD, PhD Success of clinical allotransplantation as a therapeutic option for end-stage kidney, heart, lung, and liver disease has resulted in the worldwide diffusion of this life-saving treatment However, since there are not enough cadaveric organs to meet the present clinical demand, it has also actualized the growing problem of donor organ availability Despite this shortfall, which affects all organs, the disparity between the supply and demand for organs is most acute for the lung According to the 2002 United Network for Organ Sharing registry, 3,822 patients are waiting on the recipient list in the United States for lung transplantation, and only about 1,000 of these patients will receive transplants The reasons for this frustrating scenario are the unique susceptibility of lungs to damage induced by the brain-dead treatment, the marginal yearly increase of donor lungs, and the growing number of teams performing lung transplantation As expected, access to the waiting lists is currently very restricted, patients in need of lungs are waiting approximately twice as long today as in 1990 (the median waiting period is months for patients younger than age 16 years and 23 months for those older than age 16 years), and many patients die while awaiting lungs One solution to the shortage of donor lungs would be to increase the supply of lung allografts from human sources other than cadaveric donors1 or use artificial organs, but the benefit of either as a temporary or permanent alternative to allotransplantation remains to be proven Xenotransplantation, the transplantation into humans of organs from other species, is regarded as an important solution.3 The advantages would be obvious An unrestricted number of donor lungs would be available for patients currently excluded from the waiting lists, the procedure could be planned on routine operating lists and not as an emergency procedure, the lungs would be harvested from healthy anesthetized animals rather than from brain-dead human donors on lifesustaining drugs and mechanical ventilation, the ischemic time would be minimized, and donor lungs could be genetically manipulated to minimize recipient rejection responses.4,5 History The modern era of transplantation began in the early twentieth century with the experiments of Alexis Carrel, who transplanted a variety of vascularized organs into different anatomic sites of the same animal (ie, autotransplantation) and between animals of the same (ie, allotransplantation) and different (ie, xenotransplantation) species The success observed with renal autografts demonstrated that transplantation was indeed technically feasible but also that other mechanisms were responsible for the disappointing survival results In the late 1950s, the immunological mechanisms of the immune response began to emerge and the subsequent advent of 6-mercaptopurine, azathioprine, and prednisone made kidney allotransplantation feasible This success suddenly generated a demand for renal transplantation exceeding the organ supply and, as a consequence, renewed attention toward the potential of animal organ transplantation in humans As shown in Table 31-1,6–15 pigs and nonhuman primates have been used as sources of organs, and despite the early failures, the months’ functional survival of a chimpanzee kidney transplanted into a human recipient6 clearly suggested a potential clinical application of xenografts 388 / Advanced Therapy in Thoracic Surgery Basic Immunobiology Hyperacute Rejection Experience with experimental lung xenotransplantation is quite limited in comparison with other organs, and as a consequence, the pathogenesis of lung HAR has not yet been clearly defined In other experimental discordant models, 24 the factors initiating and sustaining HAR involve an antigen–antibody interaction on the peripheral endothelium of the xenografts with subsequent complement activation via the classical pathway Once activated, the mechanism by which HAR is promoted is poorly understood; since lysis of xenograft endothelium is usually not seen, it is most probably that individual complement components, including C3a, C5a, and the membrane attack complex, initiate rapid endothelial cell (EC) activation, resulting in hemorrhage and edema of interstitial tissues and thrombosis of xenogeneic vessels The lung was once considered relatively resistant to HAR25 until further investigations proved this to be false.26 In 1995, Kaplon and colleagues reported short-term survival of baboon into which pig single-lung was orthotopically transplanted, with evidence of modest rise in pulmonary vascular resistance (PVR), acceptable gas transfers, marginal decline of xenoreactive natural antibodies (XNA), patchy deposition of immunoglobulin (Ig) M and complement proteins along the pulmonary endothelium.27 Despite significant xenograft injury (eg, intra-alveolar hemorrhage), the functional and histological absence of HAR led the authors to conclude that the lung was relatively resistant to HAR A plausible explanation of the lack of HAR would be, however, that their observations were related to xenograft hypoperfusion, since following transient occlusion of the contralateral pulmonary artery or double-lung xenotransplantation,28 all xenografts failed within 3.5 hours as a result of a tenfold increase in PVR The lessons learned from these early experiences are that studies of lung HAR should be performed with animals models where recipient survival depends on xenograft function.29–32 By contrast, Pierson and colleagues, and others, proved that pig lungs are rapidly damaged by human blood via a XNA–complement interaction and a consecutive loss of flow (PVR-related) and function.26,33 In our experimental studies, we defined the functional and histopathologic hallmarks of lung HAR using an ex vivo perfusion-and-ventilation pig-to-human lung model.34,35 Pig lungs perfused with unmodified whole human blood (WHB) showed severe pulmonary hypertension and pulmonary dysfunction as early as 30 minutes into reperfusion, massive hemorrhagic pulmonary edema, severe interstitial edema, alveolar hemorrhage, and several fibrin and platelet thrombi localized in and obstructing the small vessels (arterioles, capillaries, and venules) (Figure 31-2) but not the large (segmental or lobar) pulmonary vessels Upon immunofluorescence, there were diffuse deposits of human IgG and IgM, complement anaphylatoxins (C1q, C3a, C5a, C5b–9), coagulation proteins, and fibrinogen on the alveolar endothelial surfaces (Figure 31-3) All xenografts failed at 115 Ϯ 44.2 minutes into reperfusion These observations reinforce the paradigm that places the activation of xenograft endothelium at the center of the HAR process36 and provide evidence that pig lungs are equally susceptible to HAR as other solid organs upon reperfusion with human blood and that the front-line target of the recipient effector system is the EC located in the peripheral and not the proximal28 pulmonary vasculature Another noteworthy facet of our findings is that the HAR observed in the pig-to-human discordant model differs completely from the rejection observed in the pig-tononhuman primate 27,29–32,37 and in clinical allotransplantation between human leukocyte antigen (HLA)incompatible patients.38,39 FIGURE 31-2 Histology of pig lungs perfused with human blood A, Fibrin and platelet thrombus (arrow) within a peripheral pulmonary arteriole and located next to a terminal bronchiole (white arrow) Original magnification ϫ360 B, Multiple fibrin and platelet thrombi in an interalveolar capillary Original magnification ϫ180 390 / Advanced Therapy in Thoracic Surgery and anti-␣Gal IgG (63%) in the human blood within 30 minutes upon reperfusion These findings, not observed in pig lungs perfused with autologous blood, are in line with previous observations suggesting that IgM and IgG XNA bind the ␣Gal epitope on the xenograft’s endothelial cells and initiate HAR.4,21 However, the development of lung HAR depends on the activation of complement as well, as shown by the diffuse deposition of complements proteins C1q and C3 along the alveolar capillary walls of pig lungs and the decrease of total complement activity in the human blood shortly after reperfusion.34,35 That this step is essential for the development of HAR is suggested by the observations that inactivation of complement by cobra venom factor (CVF), soluble complement receptor type (sCR1), C1 esterase inhibitor (C1-Inh), or ␥-globulin prevents HAR and prolongs discordant xenograft survival.46 Most evidence suggests that, in pig-to-primate xenografts, the complement system becomes activated through the classical pathway (Figure 31-5) upon the binding of the XNA to the Gal ␣1–3Gal epitopes Except for situations in which the alternative pathway is stimulated by ischemia- reperfusion injury or ex vivo circuits, the alternative pathway generally does not initiate tissue injury in pigto-primate models XNA and complement activate pig EC, a protein synthesis–independent phase of the immune response, referred to as type I EC activation, and hypothesized to be the underlying cause of HAR.22 Once ECs are activated, they retract from one other, leading to changes in their physical and biologic characteristics with subsequent loss of the barrier function and normal anticoagulant property of the vascular surface This process involves the occurrence of hemorrhage and edema and exposure of the underlying collagen and subendothelial molecules Platelets adhere to and spread on the subendothelial matrix by the interaction of platelets receptors and von Willebrand’s factor (vWF), and this process is accompanied by recruitment of cells facilitating coagulation and vascular injury, such as P-selectin, plateletactivating factor, thrombin, and leukotrienes The end result will thus be recruitment of platelets and promotion of platelet thrombi and deposition of fibrin along the surface of the activated ECs FIGURE 31-5 In pig-to-primate xenografts, complement becomes activated through the classical pathway, and the cascade necessary to the development of hyperacute rejection is the assembly of the terminal components (C5b67, C5b-8, C5b-9) A key role is the formation of C3 convertase because it mediates opsonization and cell lysis leading to loss of endothelial cell function Under physiologic conditions, regulators of complement activity (RCA) such as decay accelerating factor (DAF) and membrane cofactor protein (MCP) regulate complement activation by dissociating and degrading C3 convertase CD59 prevents formation of the membrane attack complex (MAC) by blocking C9 binding to C8 Vascular Rejection If HAR can be overcome either by preventing the interaction between XNA and epitopes on xenogeneic endothelium or by interfering with the activation of complement, a xenograft is subject over the ensuing days to weeks to a rejection process characterized by EC dysfunction, interstitial hemorrhage, focal necrosis, fibrin deposition, and eventually thrombosis of the xenograft vessels This phenomenon, named “acute vascular xenograft rejection” 47 or “delayed xenograft rejection,” 48 is also observed in concordant xenografts and sometimes in allografts and differs from HAR not only in the kinetics of graft loss but also in the molecular and cellular mechanisms leading to thrombosis That the vascular rejection is initiated by the binding of XNA to the xenograft ECs has been established beyond doubt First, the onset of acute vascular rejection coincides temporally with an increase in the synthesis of XNA in subjects whose circulation is temporarily connected to a pig organ Second, XNA are diffusely deposited along the xenograft endothelium Third, removal of XNA from a xenograft recipient delays the onset of acute vascular rejection from days to weeks, and treatment of recipients with agents suppressing XNA may delay rejection for months or indefinitely On the binding of XNA to the ECs, there is a type II EC activation that involves transcriptional induction of genes and protein synthesis resulting in the expression of adhesion molecules, cytokines, procoagulant molecules, and complement components.48 The main mechanisms Lung Xenotransplantation: Lessons Learned and Future Perspectives / 391 that underlie xenograft loss caused by acute vascular rejection are thus the donor–organ EC activation and infiltration into the graft of host monocytes, natural killer cells, and the products of their activation, which collectively promote intragraft inflammation and thrombosis.48 Whether the total inhibition of XNA and complement would allow survival of discordant xenografts, if the putative T cell response is suppressed, is questioned This suggests that other factors may potentially lead to acute vascular rejection Because HAR can now be prevented in nearly all cases, vascular rejection is considered the major hurdle to the successful clinical application of lung xenotransplantation Accommodation Early attempts to transplant ABO-incompatible renal allografts showed that temporary depletion of anti-A or anti-B antibodies from the recipient in the pretransplantation period allowed prolonged graft survival in some patients even after the return of the antigraft antibodies to the circulation and despite the presence of a functional complement system This process, called “accommodation,” denotes a sort of graft resistance to humoral injury under conditions that would otherwise result in HAR or vascular rejection A similar phenomenon has been also observed in xenografts, albeit infrequently.49 The possible causes for accommodation include morphologic and functional differences between the XNA that return after depletion and the preexisting XNA, alterations in antigen expression or, more likely, an acquired resistance by xenogeneic ECs to humoral immune injury after the return of the XNA in the recipient’s circulation Cellular or Chronic Rejection To date, no reports have been published where HAR or vascular rejection have been indisputably overcome It is therefore uncertain as to whether these immune responses play an important role in xenotransplantation as they in lung allotransplantation However, experiments with murine skin and pancreatic-islet grafts, which are not subject to HAR or vascular rejection, have shown that T cell–mediated xenograft rejection is often as vigorous, or more so, than T cell–mediated allograft rejection and that conventional immunosuppressive agents may be less effective in prolonging xenograft than allograft survival.25 Strategies to Overcome HAR With the increasing understanding of its physiopathology, four basic strategies to overcome HAR have emerged, namely (1) prevention of the XNA–xenograft endothelium interaction, (2) blockage of the early steps of complement activation, (3) adhesive interactions in the coagulation pathway, and (4) pig-donor genetic engineering (Figure 31-6) Prevention of XNA–Xenograft Endothelium Interaction This can be afforded either by depleting or inhibiting the human XNA or by injecting soluble carbohydrate, saturating the XNA binding sites before engrafting The rationale for depleting XNA from the circulation of a potential xenograft recipient is the accommodation whereby discordant or ABO-incompatible grafts continue to survive despite a functional complement system and in the presence of antidonor antibody if the recipient has undergone a pretransplant depletion of antidonor antibodies Pretransplant removal of circulating XNA from potential xenotransplant recipients can be obtained by (1) plasmapheresis, (2) perfusion of human blood through pig donor organs, or (3) column immunoabsorption The first two techniques prolong pig-to-primate xenograft survival from minutes to many days.50 During plasmapheresis, red and white blood cells are isolated and returned to the primate, but all other blood elements, including the plasma containing XNA, are discarded During pig organ perfusion, the entire blood volume of a primate is pumped into the pig organ vasculature, and the XNA are removed because they adhere to the pig’s endothelium The major limitations of these techniques, however, are that they remove also the primate’s immunoglobulins and complement and coagulation proteins, thus increasing the susceptibility to infection and thrombogenic disorders Moreover, neither technique can be continued indefinitely, and the ultimate risk of immunological reactions once XNA reappear is still there Specific depletion of human XNA has been obtained by Rieben and colleagues with extracorporeal immunoabsorption (EIA) of human plasma through an immunoaffinity column of a newly developed, synthetic Gal␣1–3Gal disaccharide.51 Based on these in vitro studies, 50 to 60% of the anti-␣Gal IgM and IgA were specifically absorbed and the cytotoxic effect of human serum on pig kidney (PK15) cells was almost totally inhibited after EIA; other plasma proteins were normal through the process Similarly, in vivo studies by Taniguchi and colleagues suggested that in immunosuppressed, splenectomized baboons, repeated EIA using the same immunoaffinity column may reduce XNA levels and serum cytotoxicity significantly for several days.52 To test the validity of the above-mentioned techniques in the pig-to-human lung combination, we have developed in our laboratory an in vivo pig organ perfusion Lung Xenotransplantation: Lessons Learned and Future Perspectives / 393 colleagues.57,58 They created a large polymer with several ␣Gal epitopes incorporated (␣1–3 galactose trisaccharidepolyethylene glycol conjugate) This drug given intravenously before, during, and throughout a xenogenic pig-to-baboon transplant diminished the ␣Gal-antibodies to undetectable levels The influence of ␣Gal-antibodies could be controlled, but the remaining non-␣Galantibodies were still present and played their role in vascular rejection The new substances seem capable to overcome HAR and may lead to accommodation (not yet shown) So far, none of these results are shown in lung xenotransplantation, since there are major organ-specific differences Prevention of the Early Steps of Complement Activation Although CVF prevents HAR following pig-to-baboon heart transplantation,59 it is unlikely that these strategies will have clinical application since it is associated with unacceptable morbidity and production of anti-CVF antibodies Since these antibodies have a ␣Gal oligosaccharide as a terminal structure, there might be some anti-␣Gal antibodies, which may preclude further therapy with CVF and favor rapid xenograft rejection 60 Other soluble complement inhibitors injectable in the pretransplant period are C1 Inh, which prevents the activation of C1 by human XNA binding to pig EC and sCR1, which showed marked inhibited total and alternative pathway serum complement activity and prolonged xenograft survival in an in vivo pig-to-primate cardiac xenotransplantation model.46 In addition, the lung is particularly sensitive to ischemia and reperfusion, which is mediated in part through activation of the complement cascade.61,62 Since the lung is particularly susceptible to complement injury, and antibody-driven activation of the classical pathway is the principle mediator of HAR in other organs, 63 we reasoned that effective regulation of complement activation should be particularly effective for preventing HAR To date, there are no studies on the use of pharmacologic complement inhibitors in discordant lung xenografting, but one major disadvantage is that they must be given systemically, and in addition to preventing complementmediated xenograft injury, they may also inhibit appropriate destruction of infectious pathogens.64,65 Adhesive Interactions in the Coagulation Pathway Adhesion molecules play a critical role in ischemiareperfusion injury and mediate the lung injury seen with systemic complement activation,66,67 Where they have been examined, the interaction between most pig and human integrin and selectin ligands appears to occur under circumstances analogous to those described within either species and may thus be considered to occur in an appropriate “physiologic” manner P-selectin and intercellular adhesion molecule (ICAM-1) are examples of adhesion molecules whose function has been well characterized in this species combination and found to function physiologically.68,69 In the xenogeneic situation, other “nonphysiologic” molecular interactions may also trigger pathogenic adhesive interactions between porcine endothelium and primate platelets and neutrophils Like complement activation, activation of the coagulation cascade occurs most efficiently on activated cell surfaces Interestingly, coagulation pathway dysregulation was recently shown to play a central role in clinical acute lung injury, in that administration of activated protein C was associated with decreased morbidity and mortality from acute respiratory distress syndrome (ARDS)/systemic inflammatory response syndrome (SIRS).70–73 Several “nonphysiologic” interactions in the coagulation pathway between porcine endothelium, human platelets, and coagulation factors have been identified that are potentially important to HAR 74–78 Whereas quiescent human platelets not bind to human vWF, porcine vWF binds to human platelets through a nonphysiologic interaction via GP1b and the alpha1 domain of vWF.79 Human thrombin activation is actively inhibited by regulatory proteins on human endothelium, but constitutive activation of human thrombin occurs when human plasma is exposed to quiescent porcine endothelium Thrombomodulin and ectoadenosinediphosphatase, potent anticoagulant molecules expressed by normal endothelium, are rapidly downregulated or lost after exposure of porcine endothelium to human blood constituents, leading to a procoagulant endothelial phenotype.81,82 Porcine vWF appears to bind human complement even in the absence of antipig antibody, 83 suggesting that pig vWF itself may serve as a primary nidus for inflammation In addition, high shear stress, which occurs at sites of vasoconstriction, causes platelet aggregation to vWF and shedding of procoagulant microparticles.84 Finally, aggregated platelets coated with vWF, or vWF multimers released from the surface of injured or activated ECs, may thus activate complement in soluble phase, triggering productions of anaphylatoxins in the blood as well as where they are expressed in the organ.85 Thus even if pig endothelium is not activated by other interactions, platelet adhesion and binding of complement are likely to occur and to trigger prothrombotic and proinflammatory events in the graft and elsewhere in the organ recipient Genetically Engineered Donor Pigs The recent development of genetically engineered mice and pigs has opened several alternative approaches for the prevention of HAR.17 One large step forward to xeno- 394 / Advanced Therapy in Thoracic Surgery transplantation has been taken by generating transgenic pigs that not express the ␣Gal antigens on their ECs.5 The expression of these antigens depends on the function of a single gene encoding for the enzyme ␣1,3galactosyltransferase This gene was “knocked out” by homologous recombination, and the frontline targets for the human XNA disappeared Unfortunately, there are no data yet published about these newly designed piglets This very promising news is hopefully not overestimated because it is known from mouse ␣Gal-knockout strains that there is still a remaining ␣Gal-epitope production (about 10%) driven by an additional intracellular ␣1,3galactosyltransferase, which was recently discovered Even though some ␣Gal-epitope will still be present in theses donor pigs an important influence on HAR and vascular rejection will be seen The most promising way appeared in the past to be the development of genetically engineered pigs expressing one or more of the human C-reactive protein (CRP) 17 They include (1) decay accelerating factor (DAF), a phosphatidylinositol-linked integral membrane protein that prevents assembly of the classical pathway C3 convertase, (2) membrane cofactor protein (MCP), a membrane associate protein that serves as a cofactor for factor I-mediated cleavage and inactivation of C3b, (3) C4bBP, a soluble binding protein with decay accelerating activity for the inactivation of C3 convertase, (4) CD59 or membrane inhibitor of reactive lyses (MIRL), which prevents formation of the membrane attack complex by blocking C9 binding to C8 Because of the species-restricted molecular incompatibilities, the membrane-associated CRPs expressed on the surface of a given donor animal organ are unable to effectively control the human complement cascade, and this accounts for most of the inflammatory response observed in HAR By incorporating human complement regulatory transgenes into the germline of donor pigs, several groups have recently achieved considerable prolongation of pig heart function after heterotopic transplantation into primates 86 Parallel experience using lungs from animals transgenic for human DAF (hDAF) or CD59 (hCD59) have produced controversial results Pierson and associates found incomplete physiologic and histologic protection from HAR using transgenic pigs expressing hDAF perfused ex vivo with fresh human blood, except in two pigs expressing very high levels of hDAF on their pulmonary endothelium By contrast, Dagget and colleagues found that pig lungs expressing hDAF and hCD59 functioned better than nontransgenic pig lungs when perfused (for hours) with human plasma.37 However, in an earlier experience, Pierson and associates demonstrated that by depleting the recipient’s complement with CVF, profound pulmonary hypertension and HAR still occurred, even when human XNA depletion was added 88 These and other 89 preliminary experiences suggest that although transgenic pigs expressing CRPs at physiologically appropriate levels may prolong xenograft survival, other efforts directed to abrogate the effects of the humoral and cellular response need to be done Comment Xenotransplantation has the potential to address the acute problem of lung allograft shortage and may have additional advantages over allotransplantation Although HAR has so far prevented the clinical use of pig lungs, a combination of the outlined strategies and the new ␣Galknockout pigs offer a realistic hope that lung xenografts may survive in humans beyond the hurdle of HAR Unfortunately, while clinical trials are currently proposed or underway to address whether pig kidneys, livers, and hearts are suitable organs in humans, lung xenotransplantation is still in its experimental childhood However, some clues are available; anatomic and physiologic similarities between humans and pigs indicate that pig lungs may function adequately, at least in the short term Pig lungs are hyperacutely rejected in a similar fashion to other pig organs when perfused with untreated human blood, and despite the fact that they not have the synthetic functional problems of pig kidneys or livers, they are more prone to other nonxenogeneic injuries (eg, ischemia-reperfusion injury) than are other pig organs There are several strategies that prevent lung HAR, and there is optimism that the simplest one will be useful in a future clinical setting Nevertheless, to be of significant clinical impact and to solve the actual allograft shortage, lung xenograft survival must be at least as good as allograft survival In this sense, major areas of consideration for laboratory investigations beyond HAR need to be explored to address the long-term xenograft survival Acknowledgment This work was supported by the Immunology Concerted Action (#3026PL950004) of the Immunology Biotechnology Program from the European Union, an East-West INSERM contract and the German Research foundation (Deutsche Forschungsgemeinschaft, DFG) References Starnes V, Barr ML, Cohen RG, et al Living-related lobar lung transplantation experience: intermediate results J Thorac Cardiovasc Surg 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Alwayn IP, Appel JZ, Goepfert C, et al Inhibition of platelet aggregation in baboons: therapeutic implications for xenotransplantation Xenotransplantation 2000;7:247–57 89 Hoopes CW, Platt JL Molecular strategies for clinical xenotransplantation in cardiothoracic surgery Sem Thorac Cardiovasc Surg 1996;8:156–74 Management of Germ Cell Tumors of the Mediastinum / 423 and carbon monoxide diffusing capacity (DLCO) should be obtained before each cycle of chemotherapy containing bleomycin.63,64 A decrease in the forced vital capacity of more than 10% from baseline precludes further administration of bleomycin DLCO is very sensitive, but its decrement does not correlate well with development of clinically significant pulmonary toxicity or irreversible pulmonary fibrosis, making it less useful, unless it is severely decreased compared with baseline.65 Patients with choriocarcinoma should be monitored carefully because of its tendency to be associated with widely metastatic disease and bleeding at the sites of metastasis.23 Hemoptysis can worsen the pulmonary toxicity induced by bleomycin and severe myelosuppression can increase the risk of hemorrhage, which can be life threatening when it occurs in metastatic brain lesions In these situations, initial chemotherapy with BOP is preferable because it is effective in inducing a decrease in the tumor bulk without causing severe myelosuppression Patients with normalization of tumor markers and no residual tumor on follow-up CT scan after initial chemotherapy require no further therapy and should be followed According to the 1999 National Comprehensive Cancer Network (NCCN) practice guidelines,55 follow-up should be with tumor markers and chest radiograph monthly for the first year and every months, months, months, and months on the second, third, fourth, and fifth year respectively Follow-up can be done yearly after the fifth year CT scans of the previous sites of disease should be done every months for the first years and yearly thereafter Patients with normalization of serum tumor markers but radiographic evidence of residual disease should undergo surgical resection of the residual mass to weeks after completion of chemotherapy Likewise, enlargement of tumor masses with normalization of tumor markers most likely represents growing teratoma, and patients should undergo surgical resection.66,67 Every effort should be made to achieve complete surgical resection, including brain metastasis, because debulking resections provide no benefit and worsen the survival rate.68–71 Patients found to have only fibrosis or teratoma, after complete resection, require no additional therapy In patients with presence of viable carcinoma in the surgical specimen of a completely resected residual mass, two additional cycles of chemotherapy has resulted in long-term survival rates of 50 to 70%.68,72 Patients with incomplete remission, persistently elevated serum tumor markers, or incomplete resection of viable tumor after initial chemotherapy have a very poor prognosis with less than 10% survival rate for a median follow-up of 37 months Optimal salvage therapy for these patients has not been established Standard salvage chemotherapy with vincristine or vinblastine, ifosfamide, and cisplatin has not been proven to be of long-term benefit Several groups have shown that, contrary to testicular GCTs, salvage high-dose chemotherapy with autologous stem cell support has yielded an extraordinarily poor outcome in relapsed or refractory mediastinal GCTs and is, therefore, not indicated.73–76 Most of these patients should undergo an experimental phase I trial if available Single-agent chemotherapy with taxol or gemcitabine can be given for palliation of symptoms 7 – Nonseminomatous GCT is resistant to radiation therapy; therefore, its use in the treatment of this disease is limited at best In selected cases, there is benefit in performing surgical resection of residual tumor after chemotherapy in spite of persistently elevated tumor markers According to data from Memorial Sloan-Kettering Cancer Center, 13 patients had abnormally elevated tumor markers after completion of chemotherapy and before surgical resection Six (46%) of these patients achieved serologic remission and normalization of tumor markers after surgery Of these six, three patients are alive and with no evidence of disease All three patients had elevation in AFP only At Indiana University, 18 patients had elevated tumor markers prior to resection Sixteen of them had an elevation of AFP only One patient had elevation of both AFP and ␤-HCG, and one had elevation of ␤-HCG only Six (33%) patients remain diseasefree with a median follow-up of 43 months These six patients had an elevated AFP only, with normal ␤-HCG, prior to surgery.81 Therefore, only patients with elevated AFP are candidates for surgical resection of residual tumor after induction chemotherapy Patients with elevated ␤-HCG are not FDG PET scan can be useful in detecting residual viable tumor after initial chemotherapy, but it does not differentiate residual teratoma from fibrosis.82 High-inspired concentration of oxygen (FiO2) during mechanical ventilation for general anesthesia and overhydration should be avoided during surgery in patients previously treated with bleomycin FiO2 of 0.24 or the minimally tolerated concentration of oxygen and careful fluid replacement to avoid pulmonary edema are the current safeguard recommendations for anesthesia in patients previously treated with bleomycin.83 Treatment-Related Toxicities Toxicity from treatment is associated with the cumulative dose and the chemotherapy agents used Renal toxicity is invariably seen with cisplatin84–86 and ifosfamide87 and should be monitored closely Appropriate hydration with 424 / Advanced Therapy in Thoracic Surgery normal saline and mannitol and replacement of electrolytes are essential Pulmonar y toxicity associated with bleomycin increases with cumulative doses Doses greater than 400 units should be avoided; nonetheless, severe pulmonary sequelae have been observed in total doses below 100 units The standard treatment regimen for nonseminomatous GCT using 30 units of bleomycin per week for 12 doses carries an incidence of fatal pulmonary toxicity in young males of approximately 2% In occasional patients, pulmonary imaging studies may show discrete nodules indistinguishable from metastases These nodules may even present with central cavitation.83 Myelosupression frequently occurs with initial chemotherapy Anemia is frequent but rarely requires red blood cell transfusion in previously untreated patients Neutropenic fever occurs in 10 to 15% of patients, but it can be as high as 50% in patients treated with salvage regimens, and therefore, hemotopoietic growth factors should be given prophylactically at the beginning of salvage treatments Severe thrombocytopenia is rare with initial chemotherapy, but it can occur with salvage regimens, especially with ifosfamide.57,60,61,88–91 Acute and delayed nausea and vomiting can occur with cisplatin, paclitaxel, and ifosfamide.92 Dehydration can aggravate the nephrotoxicity of these drugs Treatment with 5-hydroxytryptamine antagonists and decadron is very effective in preventing acute emesis induced by cisplatin Delayed nausea and emesis up to days after chemotherapy may occur It is better treated with metoclopramide or prochlorperazine with diphenhydramine (for prevention of dystonia) and decadron every hours as needed Lorazepam mg every to hours may be beneficial Secondary cancers after treatment of GCT are rare Etoposide causes secondary leukemias characterized by deletions or translocations of chromosome 11q Acute nonlymphocytic leukemia occurs in 0.1 to 0.5% of patients receiving a cumulative dose of 2,000 mg/m2 of etoposide Higher cumulative doses of etoposide are associated with a higher likelihood of developing acute leukemia.46,93,94 An excess incidence of gastrointestinal tumors, mainly gastric tumors, and sarcomas has been reported in previously irradiated areas.45 The period of latency between irradiation and development of secondary solid tumors is long, and it is greatest after 10 years Fertility is an important concern, since mediastinal GCT occurs in young adults Treatment with cisplatinbased chemotherapy leads to a persistent impairment of fertility and Leydig cell function.95,96 There is subclinical Leydig cell dysfunction, with elevated levels of luteinizing hormone and follicle-stimulating hormone and normal levels of testosterone in up to 59% of patient who had chemotherapy Both the concentration of spermatozoa and the volume of the testis are significantly reduced after chemotherapy when compared with healthy men, but conception may still occur despite oligospermia If possible, sperm banking before chemotherapy should be considered for patients who plan to have children.97 Sensorimotor peripheral neuropathy can be seen with the use of cisplatin, vinblastine, and paclitaxel In severe cases, it can progress to peripheral motor dysfunction.91 Ototoxicity occurs with the use of cisplatin The earliest sign is high-frequency hearing loss and, less frequently, tinnitus.88 Raynaud’s phenomenon occurs in fewer than 10% of patients receiving bleomycin Hypomagnesemia caused by cisplatin increases the risk of Raynaud’s phenomenon.83,91,98 An increased incidence of atherosclerosis, coronary artery disease, and cardiomyopathy after radiation therapy to the mediastinum is well recognized, and it emphasizes the need to avoid mediastinal radiation therapy in patients with large seminomas.98–100 Skin toxicity is commonly seen with bleomycin and paclitaxel It may include pruritus, hyperpigmentation, hyperkeratosis (mainly on the palms and fingers), erythema, alterations of the nail bed, and skin peeling.83 Alopecia is universal and complete with paclitaxel and is common with ifosfamide, bleomycin, and etoposide MidLine Tumors of Uncertain Histogenesis These tumors are a heterogeneous group of malignancies that occur mostly in young men and have histologically unclassifiable features in a midline location Twenty-five to thirty percent of these tumors have the i(12p) or chromosome 12 abnormality, indicating a germ cell origin despite negative serologic tumor markers.101 In a series of 220 patients from Vanderbilt University, cisplatin-based combination chemotherapy resulted in 63% objective response and 26% complete response.102 The presence of abnormality of chromosome 12 predicts responsiveness to cisplatin-based combination chemotherapy and longer survival; therefore, such therapy should be obtained whenever possible.101 Immunostaining for specific tumor cell markers, cytokeratin, and placental alkaline phosphatase (PLAP) are all useful in evaluating malignant tumors of uncertain origin Other tumors with midline presentation identified by either cytogenetics or immunostaining are lymphomas, thymomas, thyroid tumors, 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nonseminomatous germ cell tumors: results of an international multicenter analysis J Clin Oncol 2001;19:1641–8 90 Bokemeyer C, Kollmannsberger C, Meisner C, et al Firstline high-dose chemotherapy compared with standarddose PEB/VIP chemotherapy in patients with advanced germ cell tumors: a multivariate and matched-pair analysis J Clin Oncol 1999;17:3450–6 428 / Advanced Therapy in Thoracic Surgery 91 Williams SD, Birch R, Einhorn LH, et al Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide N Engl J Med 1987;316:1435–40 98 Meinardi MT, Gietema JA, van der Graaf WTA, et al Cardiovascular morbidity in long-term survivors of metastatic testicular cancer J Clin Oncol 2000;18:1725–32 92 Motzer RJ, Sheinfeld J, Mazumdar M, et al Paclitaxel, ifosfamide, and cisplatin second-line therapy for patients with relapsed testicular germ cell cancer J Clin Oncol 2000;18:2413–8 99 Stover DE, Kaner RJ Pulmonary toxicity In: DeVita VT Jr, Hellman S, Rosenberg SA, editors Cancer principles & practice of oncology 6th ed Philadelphia (PA): Lippincott Williams & Wilkins; 2001 p 2912–98 93 Bajorin DF, Motzer RJ, Rodriguez E, et al Acute nonlymphocytic leukemia in germ cell tumor patients treated with etoposide-containing chemotherapy J Natl Cancer Inst 1993;85:60–2 100 Boyer M, Raghavan D Toxicity of treatment of germ cell tumors Semin Oncol 1992;19:128–42 94 Nichols CR, Breeden ES, Loehrer PJ, et al Secondary leukemia associated with a conventional dose of etoposide: review of serial germ cell tumor protocols J Natl Cancer Inst 1993;85:36–40 95 Hansen SW, Berthelsen JG, von der Maase H Long-term fertility and Leydig cell function in patients treated for germ cell cancer with cisplatin, vinblastine, and bleomycin versus surveillance J Clin Oncol 1990;8:1695–8 96 Stephenson WT, Poirer SM, Rubin L, Einhorn LH Evaluation of reproductive capacity in germ cell tumor patients following treatment with cisplatin, etoposide, and bleomycin J Clin Oncol 1995;13:2278–80 97 Lange PH, Narayan P, Fraley EE Fertility issues following therapy for testicular cancer Semin Urol 1984;2:264–74 101 Motzer RJ, Rodriguez E, Reuter VE, et al Molecular and cytogenetic studies in the diagnosis of patients with poorly differentiated carcinomas of unknown primary site J Clin Oncol 1995;13:274–82 102 Hainsworth JD, Johnson DH, Greco FA Cisplatin-based combination chemotherapy in the treatment of poorly differentiated carcinoma and poorly differentiated adenocarcinoma of unknown primary site: results of a 12-year experience J Clin Oncol 1992;10:912–22 103 Hainsworth JD, Erland JB, Kalman LA, et al Carcinoma of unknown primary site: treatment with 1-hour paclitaxel, carboplatin, and extended-schedule etoposide J Clin Oncol 1997;15:2385–93 104 Hainsworth JD, Johnson DH, Greco FA Poorly differentiated neuroendocrine carcinoma of unknown primary site A newly recognized clinicopathologic entity Ann Intern Med 1988;109:364–71 CHAPTER 35 MEDIASTINAL CYSTS DAVID C RICE, MD, BCH CESAR MORAN, MD Mediastinal cysts are relatively rare entities but are an important differential in the diagnosis of mediastinal masses In Wychulis and colleagues’ extensive review of over 1,000 patients with mediastinal masses, mediastinal cysts accounted for only 18% of cases.1 Similarly, Ovrum and Birkeland reported 91 patients with mediastinal masses, of which only 10 patients had cystic lesions (Table 35-1).2 At The University of Texas MD Anderson Cancer Center where over 2,000 thoracic procedures are performed annually, only nine patients have undergone surgery for mediastinal cysts in the last 10 years The most common location for mediastinal cysts is in the middle mediastinum; however, they may be encountered, albeit less frequently, in the other mediastinal compartments Their location is predominantly determined by their embryologic origin Thus, esophageal duplication cysts tend to occur in the middle mediastinum, pericardial cysts arise adjacent to the pericardium, and thymic cysts are found in the anterior compartment Despite their apparent rarity, the true incidence of these lesions is hard to determine Undoubtedly, in many patients cysts are asymptomatic and therefore go undetected This is particularly true for smaller cysts and those that are not in a position likely to cause tracheal or esophageal compression A broad classification of non-neoplastic cystic lesions of the mediastinum is outlined in Table 35-2 Foregut Cysts Foregut cysts represent the most common type of mediastinal cyst and include bronchogenic cysts, esophageal duplication cysts, and neurenteric cysts All result from abnormalities that occur during early embryogenesis Relative frequencies of foregut cysts compared with other mediastinal masses are outlined in Table 35-3 TABLE 35-1 Relative Frequency of Mediastinal Masses Year Author Total 1952 1956 1969 1971 1971 1972 1973 1973 1979 1980 1987 1993 Sabiston60 101 Abell4 133 Burkell61 102 Wychulis1 1,064 Fontenelle62 144 Benjamin63 216 Rubush64 186 Vidne65 45 Ovrum2 91 Nandi66 74 Davis67 400 Azarow68 257 Total 2813 Neurogenic Thymic Tumors Tumors Cysts Lymphoma Germ Cell Tumors Mesenchymal Tumors Carcinoma NOS Endocrine Other 20 43 13 212 17 49 36 19 27 57 46 548 (19%) 17 36 20 196 29 15 21 10 99 47 504 (18%) 11 12 107 39 36 14 11 62 45 352 (13%) 10 60 24 126 (4%) 10 0 25 0 34 80 (3%) 0 13 21 12 65 (2%) 17 19 12 206 25 44 51 10 10 21 67 64 546 (19%) 429 14 99 27 14 42 28 253 (9%) 36 103 12 1 27 190 (7%) Mediastinal Cysts / 431 Bronchogenic Cysts Bronchogenic cysts represent the most frequently encountered mediastinal cystic lesion (see Table 35-3) Most occur centrally, adjacent to the major airways, and intrapulmonary bronchogenic cysts are infrequent (14–23%).5,6 Their incidence has been estimated to be between in 42,000 to in 7,000 hospital admissions,7,8 although this likely underrepresents the true incidence given the fact that many lesions are asymptomatic There is a bimodal age distribution with the majority of cases presenting either in the first decade or during the third and fourth decades of life.9,10 The location of mediastinal bronchogenic cysts can be variable; however, they are usually located within the middle or posterior mediastinum at the level of the carina, or slightly inferior to it, and may be closely adherent to adjacent organs such as the tracheobronchial tree, esophagus, pericardium, or lung Cysts are usually lined by respiratory and are typically uniloculated, spherical or ovoid structures filled with fluid of varying consistency, which may be milky, greenish, brownish, or hemorrhagic, or translucent (Figures 35-1 and 35-2) If infection of the cyst has occurred there may be an intense pericystic fibrotic reaction present with dense adhesions to surrounding structures Although usually solitary, in rare instances multiple cysts may occur, and occasionally a fistulous communication may be present between the cyst and the tracheobronchial tree (less than 5%).6,11,12 Unusual locations of bronchogenic cysts that have been reported include the pericardium, thymus, diaphragm, and skin.11,13 Diagnosis Undoubtedly a large number of bronchogenic cysts are asymptomatic and remain either undetected or are discovered incidentally In the majority of published FIGURE 35-1 Photomicrograph of bronchogenic cyst showing typical respiratory epithelial lining reports, 35 to 75% of patients have symptoms In an analysis of 291 patients from published reports, 160 patients (55%) had symptoms Symptoms are generally related to the local compressive effects of the cysts on neighboring mediastinal structures In the adult population, the commonest symptom is that of chest discomfort, which is usually vague in nature, followed by cough, dyspnea, symptoms or signs of infection, and dysphagia (Table 35-4) More rarely, hemoptysis, 14 hoarseness related to recurrent laryngeal nerve compression, respiratory failure secondary to airway obstruction, myocardial infarction due to coronary artery compression15 cardiac arrhythmias, empyema, superior vena cava syndrome, or pulmonary artery stenosis may occur Radiographically, bronchogenic cysts may appear as a mediastinal widening or an intraparenchymal mass on chest radiograph An air–fluid level is frequently seen if there is a communication with the airway in cysts that become infected or following percutaneous interventions (Figure 35-3) Computed tomography (CT) scan is probably the single most useful diagnostic tool as it yields information regarding the anatomic relationships of the lesion in addition to information about its structural character Cysts typically appear as simply marginated masses with either smooth or lobulated borders (Figure 35-4).9 Low attenuation numbers (0–20 Hounsfield units) consistent with water or serous fluid are most frequently obtained The majority of bronchogenic cysts are homogenous, but cysts that have undergone hemorrhage or become infected may appear heterogenous Approximately 10% of cysts will have calcification visualized, either peripherally or in solution within the cyst (“milk of calcium”) Magnetic resonance imaging (MRI) will usually show markedly increased signal intensity on FIGURE 35-2 Resected bronchogenic cyst showing a smooth membranous suilace Mediastinal Cysts / 433 of the cyst wall may be excised and the surface of the remaining portion can be cauterized to destroy its mucosal lining, thereby limiting recurrence Incomplete excision of a bronchogenic cyst is associated with recurrence, which may occur many years after the primary procedure.12,18 Less invasive modalities may occasionally be considered Martinod and colleagues reported 20 patients with mediastinal bronchogenic cysts varying in size from to 10 cm who underwent excision using video-assisted thoracoscopy (VATS) (Figure 35-5).19 The conversion rate to open thoracotomy was 35% owing to bleeding and dense adhesions Nevertheless, in patients who underwent successful VATS resection, hospital stay was shorter and there were no significant postoperative complications or recurrences Other authors have reported similar success , Bronchial rupture was reported as a complication of VATS resection of a bronchogenic cyst by Cho and Kwack, and the authors recommend caution with the technique in the setting of significant pericystic adhesions.22 Mediastinoscopy has been reported to be useful in the excision of bronchogenic cyst.23–25 This technique is feasible for cysts in close relation to the anterior aspect of the trachea but not suitable for anterior mediastinal or posterior mediastinal cysts A further limiting factor is that it is unusual to be able to excise the cysts completely, and this is therefore a risk of subsequent recurrence If infection is suspected, mediastinoscopic resection should not be performed because of the likelihood of severe inflammation making dissection hazardous and the risk of mediastinal contamination Percutaneous aspiration, with or without the injection of sclerosants, is to be discouraged because of the high likelihood of recurrence and the danger of introducing infection or causing intracystic hemorrhage For the same reasons, if preoperative imaging studies are suggestive of a bronchogenic cyst, FIGURE 35-5 Thoracoscopic resection of a noncomplicated bronchogenic cyst arising in the posterior mediastinum diagnostic line needle aspiration adds little in terms of diagnostic information (aspirates are usually inconclusive) and may complicate any potential future surgery Esophageal Cysts Esophageal cysts account for approximately 24% of foregut cystic lesions (see Table 35-3) Palmer described three criteria for defining esophageal cysts: (1) attachment to the esophagus, (2) epithelium consistent with an alimentary tract source, and (3) the presence of two layers of muscularis propria surrounding the cyst 26 Although stratified columnar epithelium is characteristic, cysts containing intestinal, pancreatic, and gastric epithelium have been identified (Figure 35-6) In reality, the distinction between esophageal and bronchogenic cysts is not always clear-cut Both cysts may present in similar locations, and frequently the lining epithelium is nonspecific In fact, cysts with definitive bronchial epithelium have been known to communicate with the lumen of the esophagus Esophageal cysts are most commonly encountered in infants and young children and are usually located in the distal third of the esophagus.28 They are most frequently identified in infants and young children where they are often symptomatic because of compression of adjacent structures In adults, symptoms related to chest discomfort and dysphagia are more common Infection, hemorrhage, and cyst rupture may also occur Malignancy has been reported to arise in an esophageal cyst but is extremely rare.29 Diagnosis Because of their retrocardiac location within the middle mediastinum, esophageal cysts are frequently not apparent on plain chest radiographs If there is communication with the lumen of the esophagus or super-added FIGURE 35-6 Esophageal cyst lined by squamous epithelium 434 / Advanced Therapy in Thoracic Surgery infection an air–fluid interface may be visualized Indentation of the tracheobronchial tree or of the lumen of the esophagus may occasionally be seen CT scan will more accurately image the lesion Typical esophageal cysts appear as homogenous, rounded, smooth-walled structures adjacent to the esophagus Cysts are usually filled with serous fluid, unless intracystic hemorrhage has occurred, and Hounsfield units are usually in the lower range Barium esophagography may show smooth luminal indentation T2-weighted MRI will reveal high signal intensity of the cyst contents If the cyst is lined with gastric mucosa, technetium 99m pertechnetate scanning will be positive and may be useful when other imaging techniques are inconclusive Endoscopy is a useful adjunct to imaging studies, particularly for ruling out esophageal malignancy, which usually will present with mucosal involvement Esophageal cysts rarely involve the mucosa and generally appear as areas of extrinsic compression Differential diagnosis includes extrinsic compression from other mediastinal masses such as lymphadenopathy and lung neoplasms and other intramural masses such as leiomyoma if the diagnosis is in doubt Endoscopic ultrasonography can be used, which will usually demonstrate the cystic nature of the lesion.30 The temptation to biopsy the cyst should be resisted, as this may lead to infection of the cyst contents and will disrupt the usual free plane between the cyst and the mucosa of the esophagus, greatly complicating subsequent surgical resection It adds little to the diagnosis Treatment As with bronchogenic cysts, surgical excision is advised for both symptomatic and asymptomatic cysts Since most esophageal cysts occur in young children where they may impede normal development of the trachea, bronchial tree, or esophagus, excision is desirable Dysphagia is an obvious indication for excision in adults Asymptomatic cysts are best resected because if complications such as hemorrhage or infection occur, surgical excision is greatly complicated and may even require esophagectomy Aspiration of cyst contents via endoscopy has been reported; however, this is ill advised, as the cysts usually recur and there is a risk of introducing infection Such minimally invasive techniques might be considered in symptomatic patients unfit for surgery The cyst can be approached from either a right- or left-sided posterolateral thoracotomy, depending on the location of the cyst At surgery, the muscularis surrounding the cyst is incised, exposing the underlying cyst This can usually be removed without injuring the esophageal mucosa, as there is usually a free plane between the two Previous transesophageal biopsy or cyst infection may obliterate this plane and result in entry into the esophageal lumen at surgery Should this occur, the mucosa can usually be directly repaired over a 50 French Bougie with a continuous 4–0 PDS suture Following cyst excision, the muscularis is closed over the defect If the esophageal repair is in question, it should be buttressed with either pericardial fat or a pedicled muscle flap Thoracoscopic excision has been described and may be a reasonable approach for small, uncomplicated cysts.30 Prior to oral intake, adequacy of the repair is confirmed with an esophagogram Neurenteric Cysts In a review of 16 series of foregut cysts, neurenteric cysts accounted for only 2% of lesions (see Table 35-3) As described above, they are believed to be caused by an abnormality occurring during development of the notochord As such, they are frequently (70%) associated with vertebral and spinal cord abnormalities such as hemivertebrae, spina bifida, and diastematomyelia They may contain both neural and enteric tissue, including gastric mucosa Cysts may occur anywhere along the spine from the base of the skull to the first lumbar vertebra but are most common in the lower cervical and upper thoracic regions Intracranial location is rare but has been reported Cysts may be intraspinal, intradural, or extradural, and may extend through a vertebral defect into the posterior mediastinum, resulting in the so-called Kovalesky canal 32 The majority of lesions occur in a ventral position relative to the spinal cord Symptoms vary depending on the severity of the associated vertebral and spinal anomalies, and those patients with more serious vertebral and spinal abnormalities usually present in infancy In one of the larger series, motor weakness was the predominant symptom, followed by pain in the area of the lesion 33 Cases that present during adulthood generally have symptoms that occur insidiously, and it is not infrequent to discover a history of transient motor weakness during childhood Diagnosis Plain radiography may occasionally reveal vertebral anomalies CT scans will typically reveal a paravertebral cystic lesion with low Hounsfield units, and attention should be paid to any vertebral anomalies, which usually occur cephalad to the lesion MRI is the most accurate diagnostic modality for neurenteric cysts Lesions typically have low signal intensity (SI) on T1 weighted images, and high SI (similar to cerebrospinal fluid) on T2 weighted images They usually not enhance with gadolinium.32,34 Treatment Complete excision is the treatment of choice The extent of spinal involvement dictates the choice of approach For Mediastinal Cysts / 435 lesions that are predominantly intradural, a posterior approach is performed by the neurosurgical team to free the lesion from the spinal cord Depending on the extent of the mediastinal component, a posterolateral thoracotomy may then be carried out if necessary Occasionally, in cases where there is minimal spinal involvement and a dominant mediastinal component, removal through a thoracotomy is all that is necessary If the cyst is firmly adherent to the underlying neural structures, subtotal removal is advocated as there appears to be a low incidence of recurrence and this avoids the risk of neurologic injury Simple cyst aspiration is not considered appropriate therapy Pericardial Cysts Pericardial cysts are rare developmental abnormalities, which are usually discovered incidentally The incidence is estimated to be l in 100,000 They are most often encountered in the adult population and are more commonly found on the right side in the anterior cardiophrenic angle.36 The etiology of these cysts is uncertain, but they are believed to represent fusion defects of the mesenchymal lacunae, which normally bond to form the pericardium The cysts are most often uniloculated, smooth-walled cystic lesions that are lined with a single layer of mesothelial cells and are surrounded by fibrous tissue of varying thickness (Figure 35-7) Pericardial cysts usually contain clear serous fluid Symptoms are extremely rare, but there have been reports of large cysts causing pain, 37 cardiac tamponade, 38 and dyspnea 39 Radiologically, pericardial cysts appear as wellcircumscribed rounded masses that abut the heart A characteristic teardrop shape is described on lateral projection because the lesion tends to conform to the medial aspect of the oblique fissure CT scan reveals a unilocular homogenous low attenuation lesion with a thin, smooth wall adjacent to the pericardium Further spatial relationships between the cyst and the cardiac structures may be obtained with echocardiography In addition this will often yield useful information regarding possible tamponade effect in cases that are symptomatic Observation is usually recommended for asymptomatic cysts Percutaneous aspiration may be considered for acutely symptomatic lesions In cases of diagnostic uncertainty and of symptomatic cysts, definitive resection via a posterolateral thoracotomy or VATS approach is indicated than pericardial tissue Therefore they tend to be more thin-walled and friable They are rarely, if ever, symptomatic and therefore may usually be observed Radiographic studies are usually diagnostic; however, if uncertainty remains, the lesions may be aspirated under CT or ultrasound guidance The finding of clear, serous fluid is diagnostic Thoracic Duct Cysts Thoracic duct cysts are rare entities, and less than 30 have been described in the literature Most occur in the posterior mediastinum along the course of the thoracic duct, but occurrence in the anterior mediastinum has also been documented.40 Although thoracic duct cysts are usually asymptomatic, they may cause compression of the superior vena cava, esophagus, and tracheobronchial tree One report describes acute postprandial tracheal compression presumably related to increased chyle production following fat ingestion.41 The cyst usually contains cloudy serous fluid, with a high lymphocyte count and elevated triglyceride levels (> 100 md/dL) Histologically, the cysts are lined with a monolayer of endothelial cells (Factor VIIIrelated antigen positive) surrounded by smooth muscle cells and islets of lymphoreticular tissue.42 Preoperative diagnosis is rare CT scan reveals a smooth-walled, wellcircumscribed cystic structure but cannot accurately differentiate it from other mediastinal cystic lesions The majority of the reported cases have been treated surgically, and it is important to ligate all afferent and efferent lymphatic channels to prevent postoperative chylothorax.43 One report documented recurrence years after percutaneous aspiration, suggesting that these lesions require definitive excision Indications for resection include uncertainty of diagnosis and the potential to cause compressive symptoms Pleural Cysts Pleural cysts are usually described in conjunction with pericardial cysts as “pleuropericardial cysts.” Rarely, an isolated serous fluid–filled pleural cyst may be encountered The cysts are similar histologically to pericardial cysts except they are covered with parietal pleura rather FIGURE 35-7 Pericardial cyst lined by low cuboidal-type epithelium 436 / Advanced Therapy in Thoracic Surgery Parathyroid Cysts those located within the late mediastinum usually require a thoracotomy or median sternotomy The cysts frequently are in close proximity to the recurrent laryngeal nerves, and extreme care must be exercised in their removal As with the removal of any hyperfunctioning parathyroid tissue, postoperative serum calcium levels require close monitoring because of occasional rebound hypocalcemia due to the other normal but physiologically suppressed parathyroid glands The first reported removal of a parathyroid cyst of the mediastinum was in 1925 by de Quervian.44 Although rare, parathyroid cysts are an important differential in the diagnosis of anterior mediastinal cystic lesions Their clinical significance is heightened by the fact that up to 40% may be hyperfunctioning, resulting in the protean symptoms and signs of hyperparathyroidism Parathyroid cysts vary in size, but in a recent review of 93 patients by Shields and Immerman, the mean diameter was cm.45 The majority of cysts are thin-walled and contain clear serous fluid, the cysts are lined with a single epithelial layer, and parathyroid tissue may be found within the overlying mural fibrous tissue (Figure 35-8) In the review by Shields and Immerman, the majority of cysts were located within the anterosuperior space (59%), with the remainder residing in the middle mediastinum (28%) or the anterior mediastinum (13%), occasionally within the thymus Embryologically, most anteriorly located parathyroid cysts are believed to be the result of abnormal migration of one of the inferior parathyroid glands during descent from the third branchial pouch Occasionally the cysts represent supranumerary parathyroid tissue Superior glands (from the fourth branchial pouch) are involved in up to 20% of lesions located within the middle compartment The cause of cyst formation is unknown but may represent cystic degeneration of a parathyroid gland or preexisting adenoma or hyperplastic gland Apart from the symptoms of hyperparathyroidism, cysts may also cause compression of neighboring structures, including recurrent laryngeal nerve paresis There has been a single report of carcinoma arising within a parathyroid cyst Surgical resection is the mainstay of treatment Cysts located in the anterosuperior space can usually be removed from a cervical approach, whereas Thymic cysts account for less than 1% of mediastinal cystic lesions46 and are usually found incidentally on chest radiographs Although usually asymptomatic, they can occasionally cause dyspnea related to tracheobronchial compression, recurrent laryngeal nerve paralysis, dysphagia and left brachiocephalic vein obstruction.47 Cysts may occur anywhere along the embryological line of descent of the thymus, from the hyoid to the anterior mediastinum Although usually small, cysts as large as 30 cm in diameter have been recorded.48 The cysts are usually thinwalled and unilocular but may also be multiloculated and have walls of varying thickness (Figure 35-9) Radiographic appearance is that of a smooth, wellcircumscribed mass, usually in the anterior compartment CT scan reveals a homogenous, uniloculated cystic lesion with variable amounts of surrounding soft tissue Thymic cysts appear to have a propensity for intracystic hemorrhage, and this may lead to a heterogenous, more solid appearance on CT scan MRI adds little to the diagnosis Because of their location, thymic cysts are readily biopsied percutaneously Absence of parathyroid hormone or thyroglobulin may rule out parathyroid and thyroid cysts, but there is no reliable indicator of the cysts thymic origin.49 Surgery is recommended as definitive FIGURE 35-8 Parathyroid cyst with portion of normal parathyroid tissue FIGURE 35-9 Unilocular thymic cyst with smooth glistening surface Thymic Cysts Mediastinal Cysts / 437 treatment for all symptomatic and most asymptomatic thymic cysts Aspiration alone is associated with cyst recurrence Furthermore, there have been numerous reports of association between thymomas and thymic cysts, and current diagnostic imaging techniques are inadequate for differentiating benign cystic lesions from neoplastic ones A single case of thymic carcinoma arising in a thymic cyst has been reported 50 Operative approach is dictated by the size and location of the thymic cyst but is usually via median sternotomy or posterolateral thoracotomy Multilocular thymic cysts (MTCs) are distinctive entities, which pathologically and probably pathogenetically are different than congenital thymic cysts Histologically they are quite different from congenital lesions and are characterized by the presence of prominent hyperplastic and inflammatory changes (Figure 35-10) Thus, it is believed that this lesion represents an acquired reactive process, which may lead to the cystic transformation of thymic medullary duct epithelium–derived structures One important characteristic of MTCs is that they often extend to adjacent structures, simulating an invasive neoplasm In a few cases, recurrences after incomplete removal of the lesion have been documented Hydatid Cysts Primary hydatid cysts usually occur in the liver, lungs, kidney, and brain.51 Hydatid cysts in the mediastinum are extremely rare and account for only 0.1 to 0.4% of all cases In a large series by Kabiri and colleagues, only of 2,332 (0.3%) intrathoracic hydatid cysts occurred in the mediastinum.52 The tapeworm responsible for hydatid disease, Echinococcus granulosus, is most common in the sheep- and cattle-raising regions of the world, such as Australia, New Zealand, South Africa, South America, and the Mediterranean Humans act as an intermediate FIGURE 35-10 Multilocular thymic cysts showing prominent lymphoid hyperplasia host for the Echinococcus larvae Infection occurs either through contact with a definitive host or by the ingestion of contaminated vegetables Intrathoracic cysts may reach a large size Hydatid cysts have recently been categorized into three groups 53 : Type I cysts are primary lesions composed of three separate layers: an outer layer, or pericystic layer, composed of reactive and compressed surrounding host tissue; a middle, smooth, whitish laminated layer; and an inner germinal membrane, which produces the laminated layer and scolices Type II cysts occur when daughter cysts develop within the original type I cyst (Figure 35-11) Type III cysts represent cysts that have involuted and died Small lesions may be asymptomatic; however, larger cysts may cause symptoms related to compression of surrounding structures Fever is uncommon unless rupture has occurred Rupture may also lead to anaphylaxis, hydatid dissemination, and secondary bacterial infection Radiographically, cysts appear as radiopaque smoothwalled spherical structures unless rupture has occurred Cysts that communicate with the lung parenchyma may demonstrate intracystic air if rupture occurs Air tracking between the pericystic layer and the laminated layer produces a characteristic superior-based semilunar lucency called the “crescent sign.” An air–fluid level may form within the cyst cavity with the collapsed cystic membranes floating on the surface of the residual fluid, leading to the so-called “water filly sign.” If free rupture occurs into the pleural space, patients may present with radiographic evidence of pleural effusion or hydropneumothorax CT scanning more accurately reveals the spatial relationships and characteristics of the cyst Koul and colleagues reported CT densities ranging from Ϫ40 to 160 Hounsfield units (median 15.5 HU) and the majority of cases had walls ranging in thickness less than FIGURE 35-11 Type II hydatid cyst showing daughter cysts and the cyst lining 438 / Advanced Therapy in Thoracic Surgery 10 mm.54 Serologic testing using a specific immunoglobulin G (IgG) ELISA and immunoelectrophoresis (IEP) is the most sensitive laboratory test available with reported sensitivities of 97 and 100% respectively Treatment of hydatid cysts is primarily surgical, and chemotherapy using either mebendazole (20–40 mg/kg/d) or albendazole (10–14 mg/kg/d) is used in an adjunctive manner Surgical treatment has two goals: (1) the removal of the hydatid cyst and (2) adequate sterilization for removal of the surrounding pericystic membrane One of two methods is generally employed The first involves carefully incising the pericystic membrane until the laminated layer is reached The cyst is then carefully enucleated intact, leaving the pericystic membrane in place The second method involves aspirating the cyst and then widely incising it Hydrogen peroxide or hypertonic saline is then instilled to sterilize the germinal layer and any remaining scolices, following which the laminated and germinal layers are removed Before excising the cyst, the operative field should be covered with gauze packing to prevent potential contamination of surrounding areas with cyst contents The remaining pericystic cavity can be obliterated using a series of purse-string sutures, a technique called “capitonnage.” Recurrence rates of appropriately excised intrathoracic hydatid cysts are low (< 3%).55 shows a smoothly marginated cystic mass with density similar to water Higher attenuation, particularly after contrast injection may be due to volume averaging caused by the mixture of low-density fluid and higherdensity lymphatic vessel walls, particularly in the case of cavernous forms MRI findings typically show signal similar to muscle on T1 weighted images and markedly increased intensity on T2 weighted images Surgical excision, usually via a median sternotomy or thoracotomy incision, is indicated for diagnostic purposes.59 Lymphangioma St Georges R, Deslauriers I, Duranceau A, et al Clinical spectrum of bronchogenic cysts of the mediastinum and lung in the adult Ann Thorac Surg 1991;52:6–13 Lymphangiomas are benign lesions of lymphatic origin that usually occur in the neck and axillary regions Mediastinal involvement is rare, and the lymphangiomas represent only 0.7 to 4.5% of all mediastinal tumors Their etiology is unclear and it is uncertain whether they represent congenital, hamartomatous, or neoplastic lesions.56,57 Mediastinal presentation is more common in adults than in children Although some cases may represent recurrence after incomplete resection of childhood lymphangiomas, many patients have no history of previous lesions Lymphangiomas are usually cystic lesions and may consist of a single large macroscopic lymphatic space (hygroma type) or a collection of smaller multilocular cysts (cavernous type) They are classically described as occurring in the anterior and superior mediastinum.56 Although a recent report by Charruau and colleagues documented that the right 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