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Lymphology 50 (2017) 114-119

LYMPHSPIRATION / EDITORIAL

LYMPHANGIOLEIOMYOMATOSIS AND GORHAM-STOUT DISEASE: PRIMARY OR SECONDARY DISORDERS OF THE LYMPHATIC SYSTEM?

M.H. Witte

Department of Surgery, University of Arizona College of Medicine, Tucson, Arizona USA

ABSTRACT Lymphangioleimyomatosis (LAM) is a diffuse pulmonary disease typically featuring Lymphangioleimyomatosis and Gorham- hyperplastic smooth muscle-invested intra- Stout disease, rare disorders which share pulmonary and extrapulmonary lymphatics features of proliferating lymphatic vessels, and associated with a variety of extra- predominantly in the lung in the former and pulmonary benign vascular tumors. Gorham- bone in the latter, commonly manifest as Stout disease (GSD) or “disappearing bone” progressive lung disease often associated with is usually (but not always) associated with life-threatening complications of chylous single or multifocal lymphangiomas reflux from central lymphatic obstruction/ [overlapping the spectrum of generalized leakage. This Lymphspiration-Editorial lymphangiomatosis (GLA) with bone involve- proposes that, rather than a secondary compli- ment] and often associated with progressive cation, lymphatic obstruction/ dysfunction is lung disease. The clinical and pathologic a much earlier or even the primary event in features and their progression implicate the the pathogenesis of both disorders and that lymphatic system and specifically lymphatic lymphostasis drives the cellular proliferative obstruction as a common component of response in both lung and bone and even both disorders contributing to substantial distant sites. morbidity and mortality (1,2). They also raise the conundrum of “benign metastases,” Keywords: Lymphangioleiomyomatosis a seeming contradiction of terms. (LAM), Gorham-Stout disease (GSD), The key question, and one with important generalized lymphangiomatosis (GLA), clinical implications, hinges on the exact benign metastasis, lymphangioma, sequence of events in the pathogenetic process: lymphatics, lymphostasis, pathogenesis, Does lymphatic obstruction/lymphostasis imaging, treatment precede (“primary”) rather than follow early or late (“secondary”) the pleiomorphic In this, previous, and forthcoming issues cellular proliferative (hyperplastic, neoplastic, of Lymphology, lingering and fresh insights ‘”metastatic”) phase of each disease? Within raise intriguing questions about the primacy the limitations of current lymphatic imaging of the lymphatic system and the very nature protocols and accurate inclusive reporting of two rare and often fatal disorders. of clinical details of these rare conditions,

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and regional lymph nodes (LAM) and in bone (GSD) (normally lacking lymphatics), associated with tissue fibrosis. On the other hand, the “proliferative theory” posits that lymphatic obstruction is secondary and a much later life- threatening event. Driven by a variety of “triggers” – gene mutations, wound/fracture healing, vascular growth factors and assorted hormones and cytokines – albeit inconsis- tently documented, lymphatic, vascular accessory cell, smooth muscle (pericyte), and pluripotential stem cells are turned on to the proliferative mode, and in the walls and lumen of pulmonary and extrapulmonary lymphatics produce vessel narrowing and obstruction. This proliferative process is viewed by some as not only neoplastic but actually fulfilling the definition of cancer (10), particularly as cells and cell clusters migrate through the interstitium, enter the lymph circulation, deposit in lymph nodes, Fig. 1. Photomicrograph of a thoracic duct accumulate in body cavity fluids, and appearing grossly normal but exhibiting extensive circulate in the blood stream to arrive or arise obstructive intraluminal proliferation of smooth muscle cells in an autopsy examined specimen from in distant and even select locations (e.g., a patient with LAM (H&E x40). (Reproduced from bone), thereby behaving like true “metastases” ref. 9 with permission and modified legend.) but “benign” by most other criteria. What is known about the proliferative potential (hyperplasia, dysplasia, neoplasia) of the support for the “primary” view comes from primary and metastatic lesions and masses in various multimodal imaging techniques. LAM (10,11) and GSD (2,12) and are in vitro Conventional oily contrast lymphography, cultures an accurate reflection of in vivo lymphscintigraphy, and MRI have all been biologic behavior? Indeed, some lesions (and used to document the frequent anatomic and patients) remain stable for long periods of functional abnormalities in the central time without treatment, circulating VEGF-C lymphatic system (thoracic duct and larger and -D levels are often elevated, and clinical tributary collectors) and specifically improvement with lesion regression has lymphatic obstruction, lymphostasis, lymph been reported with the use of targeted anti- reflux, collateralization, and external fistulae (vascular) growth factor therapy in both LAM in both LAM and GSD (1-7). Histologic and and GSD and recurrence with discontinuation immunohistochemical reports from biopsy, of these agents. Furthermore, is proliferation surgical, and autopsy specimens with and of the putative responsible/errant (non- without lymphatic-specific staining (1,2,8,9) lymphatic) cell type (vascular smooth muscle) further delineate microscopic lymphatic a primary event? What is that cell of origin abnormalities – increased numbers, lymphan- and its relationship to other parenchymal or giectasia, thickened walls, intramural and mesenchymal cells – e.g., in the lung and extramural obstruction, and dysplasia in airways or in the bony skeleton or encircling the lung and lymphatic collectors (Fig. 1), and extramurally obstructing these lymphatic

Permission granted for single print for individual use. Reproduction not permitted with permission of Journal LYMPHOLOGY. 116 channels? How interchangeable and trans- overgrowth phenomenon. The sequelae of formable are cell types by transdifferentiation? lymphatic obstruction in a variety of organs Is not the (lymph)angioblast one of the as well as in the limbs are by now well- most primitive “stem cells”? Our interest in recognized. These “lymphostatic disorders” these questions began in 1982, when we were elegantly characterized by Földi and encountered a young woman presenting in colleagues more than a half century ago (14), extremis with a giant cervicomediastinal further conceptualized by us (Fig.2) in the lymphangioma associated with extensive 1980’s (15), and underlying molecular bony lesions (osteoclastic “metastases”) mechanisms are currently being investigated. throughout her skull and skeleton. The Just as during obstruction of blood vascular primary mass of chylous and non-chylous flow, internal stress and elevated intraluminal cystic structures wrapping around the lungs pressure in anatomically or functionally and heart was meticulously resected obstructed lymphatic vessels act as potent almost in its entirety from jaw to diaphragm. stimuli to (lymph)angiogenesis/vasculogenesis We subsequently cultured lymphatic with increasing smooth muscle remodeling in endothelial cells from the mass and observed the hypertensive vessel wall. With persistence for the first reported time what we termed of lymphostasis, a sequence of events is set “‘lymphangiogenesis’ (in contrast to heman- into motion characterized by accumulation of giogenesis) in vitro”. Clusters of these cells high protein lymphedema, immune dysregu- sprouted tubes in tissue culture spontaneously lation, inflammation, susceptibility to without added growth factors or special infection, and soft tissue overgrowth - with matrix and survived for many generations fibrous and adipose deposits – accompanied (12). Her disorder would subsequently be by vigorous lymph- (and often also hem-) recognized to fall under the diagnosis of GSD angiogenesis and later, angiotumorigenesis. (12,13). Remarkably, 35 years later, her Warty overgrowths and benign tumors disease remains stable without recurrence of appear and in rare instances, angiosarcoma the primary cervicomediastinal tumor and and other malignancies as cells transition with neither expansion not regression of her [epi(endo)thelial- mesenchymal transition – widespread “benign metastatic” bone lesions. EMT] into altered migrating phenotypes A bold surgeon’s debulking of the primary capable of entering the lymph circulation tumor (and no other treatment) abruptly with dissemination to the bloodstream and halted the “proliferative” stimulus and the distant sites (13,15). metastatic process! The suggested fundamental shift in Relatively unexplored is the concept perspective about both LAM and GSD would that the “proliferative stimulus” in LAM stimulate different and innovative approaches and GSD might be secondary to a hidden to early evaluation, treatment and even “primary” but as yet inadequately studied prevention that might also alleviate other lymphatic obstructive process? Lymphatic features of these diseases – in the lung and obstruction itself leads to the known sequelae bones – that follow the common pathway of of “lymphostasis” which could mimic the “lymphostasis”. This line of thinking was “proliferative theory.” Mechanistically, reinforced at the 2nd International Conference lymphostasis with high protein (lymph)edema of the Lymphatic Malformation Institute in fluid accumulation and the associated Atlanta in June 2016 (16), when review of loosening of the sol-gel extracellular matrix, the comprehensive database registry for GSD stimulates vigorous lymphangiogenesis and revealed that chylothorax with progressive even lymphatic cellular transdifferentiation lung disease and other chylous reflux compli- and cellular migration as part of a more cations were the chief causes of death and generalized or even selective/targeted tissue serious morbidity rather than the distinctive

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Fig. 2. Schematic diagram proposing pathophysiologic links between lymphangiogenesis and lymphangiodysplasia, hyperplasia, and neoplasia in the setting of lymphostasis. During a latent period, lymphatic dysplasia produces ectasia, muscular dysfunction, paralysis, and valve incompetence culminating in persistent high-protein lymphedema. Subsequently, superimposed opportunistic infection, immunosuppression, and injury with recurrent lymphangitis promote persistent lymphedema, intense angiogenesis, lipid deposition and fibrosis, and on rare occasions malignant vascular neoplasia. This sequence of events may occur as a local phenomenon in peripheral lymphedema or in a multitude of isolated or generalized visceral disorders characterized by scar formation, angiohyperplasia, and neoplasia. (Reproduced with permission from ref. 15)

“disappearing bone.” There was a call for reflux into the lung [what Dori and Itkin early diagnosis and early intervention when have called “lung perfusion” (a special form these “secondary lymphatic complications” of lymphedema) seen on magnetic resonance first appear and even “preventive” lymphatic lymphograms] (17) may initiate progressive imaging screening beforehand (but could pulmonary dysfunction, proliferation of these actually be “primary”?). In this light, diverse cell types, and pathologic changes in as mentioned earlier, the limited but often both LAM and GSD. Furthermore, lymph temporary success of therapy with anti- and particularly chylous lymphostasis/reflux proliferative agents like rapamycin (sirolimus) surrounding or within bone may also stimu- in both disorders could perhaps be viewed as late the aggressive osteoclast proliferation attacking the secondary effects of lymphatic responsible for “disappearing bones” in GSD. obstruction/lymphostasis, which include pro- Eliminating the lymph reflux by interventional liferation of a variety of cell types particularly lymphatic sclerosis therapy or lymphovenous lymphatic endothelium (i.e., secondary decompression (diversion) would be predicted lymphangiogenesis/ lymphvasculogenesis) to abort this chain of events. Interestingly, and pericytes. Indeed, continued chylous older articles referred to LAM as chylous lung

Permission granted for single print for individual use. Reproduction not permitted with permission of Journal LYMPHOLOGY. 118 disease and GSD as “chyle in bone” but the expression “benign metastasizing these terms were later abandoned as specific lymphangioma” remain unresolved. Without non-lymphatic cell types (myoepithelial cells, improvement in understanding and this pericytes, or osteoclasts) and molecular possible paradigm shift, introduction of novel events became the focus of investigation and therapies will not be available that might even targeted treatment. improve prognosis, quality of life, and life Until non-invasive lymphatic imaging is expectancy for patients afflicted with these carried out more widely, earlier in the course perplexing disorders. Lymphologists all over of disease, and with enhanced spatial and the world need to bring together their temporal resolution of dynamic images – and experience, knowledge, technology and skills this would seem to be indicated now – the (particularly in diagnostic and interventional nature of these disorders and approaches to imaging and decompressive lymphatic management based on preventing or reversing surgery) to positively impact patients with the life-threatening lymphatic abnormalities LAM and with GSD. will likely remain elusive. If the “primary” lymphatic obstructive hypothesis holds true CONFLICT OF INTEREST AND or applies much earlier in the disease than DISCLOSURE currently suspected, then screening of lymphatic abnormalities even before they The author declares that no competing manifest clinically – particularly chylous financial interests exist. and non-chylous reflux and “lung perfusion” REFERENCES – by biplanar lymphangioscintigraphy preferably with SPECT-CT localization is 1. Gupta, R, M Kitaichi, Y Inoue, et al: indicated. Furthermore, image-guided radio- Lymphatic manifestations of lymphangioleio- logic (lymphatic sclerosis) (17) or operative myomatosis. Lymphology 47 (2014), 106-117. interventions such as lymphatic decompres- 2. Dellinger, MT, N Garg, BR Olsen: Viewpoints on vessels and vanishing bones in Gorham- sive (lymphatic-venous) shunts (18) or Stout disease. Bone 63 (2014), 47-52. “tumor debulking” (12) should be considered 3. Baulieu, R, G de Pinieux, A Maruani, et al: earlier in the course of these diseases rather Serial lymphoscintigraphic findings in a than focusing on controlling (with attendant patient with Gorham’s disease with lymph- edema. Lymphology 47 (2014), 118-122. adverse side effects) the secondary prolif- 4. Lohrmann, C, E Foldi, J-P Bartholoma, et al: erative effects of lymphatic obstruction and Disseminated lymphangiomatosis with lymphostasis in affected organs. skeletal involvement: Detection with magnetic resonance lymphangiography. Lymphology 40 In summary, the fundamental (2007), 74-80. unanswered question remains: are these 5. Wang, R: The value of multi-detector primarily lung, bone, or congenital or computed tomography direct-lymphangio- acquired lymphatic/vascular disorders? Is graphy in pulmonary lymphangioleiomyoma- tosis. Abstract book of the 24th International lymphatic obstruction with or without lymph Congress of Lymphology, Rome, 2013. p 71. reflux, lymphatic overgrowth, or tumor (Online) http://www.lymphology2013.com/ formation (with “metastasis”) simply secon- Abstract-Book/. dary to parenchymal involvement and trans- 6. Wang, R: CT and MRI findings of skeletal abnormalities associated lymphatic dysplasia. differentiation of cell types in the primary Abstract book of the 24th International neoplastic process or is it the primary Congress of Lymphology, Rome, 2013. p 71. phenomenon? Moreover, the overlapping (Online) http://www.lymphology2013.com/ biomarkers and processes that define Abstract-Book/. 7. Huo, M, W Zhen-chang, Y-L Yue, et al: neoplasia, cancer, and embryonic develop- Imaging features of vaginal chylous fistula in ment of the lymphatic system as well as the lymphangioleiomyomatosis: A case report. seeming contradiction of terms that underlie Lymphology 50 (2017), 136-140.

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