Case 3a -

Lymphatic Malformation Harry Kozakewich Children's Hospital Boston Boston, MA

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Clinical History: This 10 month old boy was born with a soft tissue mass lateral to the left breast which was stable until the week before excision when it was noted to increase in size. There was no fever or tenderness. A 6cm subcutaneous mass was excised in 1976 from which the images are taken. A recurrent mass was excised in 1992. Case 3a - Figure 1 Case 3a - Figure 2 Case 3a - Figure 3 Case 3a - Figure 4 Differential Diagnosis: 1. Lymphatic malformation 2. Venous malformation Pathologic Findings: The submitted images depict mostly small channels with thin walls with no muscle and lumens that are either empty or contain protein or lymphocytes. A large channel (or cyst) is present that is devoid of endothelium but has a thick wall of loose fibrous tissue and strands of smooth muscle. The stroma contains collections of lymphocytes, often in a perivascular location. The histologic picture is quite typical of a lymphatic malformation (LM) of the micro/macrocystic variety. However, it may be difficult to tell these apart from blood vascular lesions, particularly venous malformations because luminal content may be misleading. LM channels may be filled with blood from trauma or perhaps spontaneously and sometimes contain organizing thrombi; venous malformations may have empty lumens from blood draining post-excision. For these reasons, it is often necessary to do an immunoperoxidase stain for podoplanin (D2-40) or Prox-1, both of which are positive in the endothelium of LMs and normal lymphatic vessels. Final Diagnosis: Lymphatic malformation Discussion: Lymphatic malformations (LMs) are developmental anomalies of the lymphatic system that have in the past been called lymphangioma or cystic hygroma depending on whether the size of the channels was small or large, respectively, and also lymphangiomatosis if involvement was generalized. Many are noted at birth and most are evident by the age of 2 years. Most commonly, the soft tissues of the axilla, chest, and cervicofacial region are affected, but the mediastinum, retroperitoneum, buttock, and anogenital area are also common sites. Adjacent skin and mucosa are frequently involved. The extent of LMs varies from small, localized sponge-like lesions to diffuse involvement of a region or organ, to generalized involvement including viscera and bone. They are classified as microcystic, macrocystic (spaces larger than 1cm), or combined. [1] Some LMs enlarge with time, and this is believed to be caused primarily by distention with fluid. The proliferative index is negligible or low-level. [2] Certain features of LM reflect the abnormal development of the lymphatic system. Localized LMs of the skin and subcutis have blind subcuticular lymphatics that do not connect with the deep (intramuscular) lymphatics. [3] In extensive or generalized lesions, abnormalities of large lymphatic trunks including the thoracic duct, such as ectasia, lack of valves or atresia, have been demonstrated. [4, 5] LM may be encountered in other syndromes such as Trisomy 21 and Noonan and is an invariably prominent component in Klippel-Trenaunay syndrome. In general, the histologic pattern in LM is characterized by channels of varying size with an attenuated endothelial lining although there may be foci with more "active" cuboidal endothelium. The smallest channels are lined by endothelium that rests on stromal collagen and larger ones have a thin and irregular muscular coat. Large macrocystic or unilocular LM usually have a thick wall composed of fibrous tissue with myofibroblasts, a few smooth muscle cells and interstitial ground substance. Lumina may be empty, contain a lacy pale or dense eosinophilic protein, lymphocytes or occasional macrophages containing red cells or hemosiderin. Sometimes, lumina contain blood from trauma, the operative procedure, or communication with the venous system. Imunoperoxidase markers have proven invaluable in helping to differentiate LMs from other vascular anomalies, particularly venous malformations. Antibodies to Prox-1 and VEGFR3 are reported to be superior to D2-40 (podoplanin) or LYVE-1 in staining of the endothelium in LMs, particularly in staining of large channels which usually stain focally or not at all with the latter two antibodies. [6] In contrast, the endothelium of arteries and veins is negative with these 4 antibodies. Immunoreactivity in LMs for CD31 and Factor Vlll-related antigen is patchy and variable and for CD34 is usually faint or absent. The cutaneous form of LM (the older term is "lymphangioma circumscriptum") is seen clinically as crops of hyperkeratotic papules, usually localized to one area. The papillary dermis is expanded by thin-walled channels frequently producing verruciform hyperplasia, ulceration, infection, inflammation, hemorrhage and thrombosis. Often, the deeper dermis and subcutis are also involved but channels in these locations are usually larger with thin muscular walls. The stroma often contains pools of lymphocytes and sometimes lymphoid follicles with or without germinal center. Plasma cells and polymorphonuclear cells may also be present following infection. The dermis is usually thickened, the subcutaneous fibrous septa is expanded, and there is an increase in subcutaneous fat. The abnormal lymphatics have absent or impaired connection with the deep (intramuscular) lymphatics. [6] Generalized LM (in clinical practice sometimes also called "lymphangiomatosis"), is defined as an extensive lymphatic anomaly, usually involving extremities, retroperitoneum, and mediastinum. Organ systems are commonly involved, particularly spleen, pleura/lung, liver and intestine. Fistulae can develop between serous cavities and thoracic, cisterna chyli or other large lymphatic channels causing effusions. Serous effusion, pulmonary involvement, and vertebral compression can dominate the clinical presentation. This disorder can manifest at any age and is often fatal. [7] The histopatholgy is similar to solitary or isolated LM, but in some lesions, the channels are smaller and more numerous, complex and permeative. The lymphatic endothelium tends to have slightly larger nuclei and more abundant cytoplasm, and focal endothelial hyperplasia with pseudopapillary and papillary formation may be present. The proliferative index is low, but is increased where there is cellular enlargement and hyperplasia. Visceral LMcan occur as a solitary lesion in any organ, excluding the central nervous system (which lacks lymphatic drainage). The small bowel mesentery is a common location and while most are not strictly "visceral", some multicystic ones also involve the wall of the bowel. [8] So-called primary "intestinal lymphangiectasia" can be localized to variable lengths of the bowel and is often associated with more widespread LM, often generalized LM. [9] Osseous involvement by LM may be solitary or multifocal in generalized LM, whereas in Gorham-Stout disease, it is regional usually affecting multiple contiguous bones. Solitary LM may be microcystic, macrocystic, or both. The histopathology in generalized LM is similar to that encountered in the soft tissue and viscera. [10] In Gorham-Stout syndrome, also known as "disappearing bone disease" and "phantom bone disease", [11] one or more axial or long bones, often contiguous, gradually demineralize and "disappear". In our experience and that of others, [12] it is almost invariably associated with an extensive LM of adjacent soft tissue and often generalized LM. Attention has been drawn to the apparent important role of osteoclastic activation by various cytokines in this disorder. [12] Histopathology shows abnormal, generally small caliber lymphatic channels in the adjacent soft tissue and periosteum extending into bone. The bony trabeculae are thinned, there is osteoclastic absorption of existing bone as well as new bone formation, and the loose fibrous stroma has lymphocytes and plasma cells. [13, 14] Late lesions show fibrous tissue of bone. [15] References: Mulliken JB, Fishman SJ, Burrows PE. Vascular anomalies. Curr Probl Surg 37:517,2000. Meijer-Jorna LB, van der Loos CM, de Boer OJ, et al. Microvascular proliferation in congenital vascular malformations of skin and soft tissue. J Clin Pathol 60:798,2007. Whimster IW. The pathology of lymphangioma circumscriptum. Br J Dermatol 94:473, 1976. Kinmonth JB. The Lymphatics. London: Edward Arnold, 1982. Fishman SJ, Burrows PE, Hendren WH. Life-threatening anomalies of the thoracic duct: anatomic delineation dictates management. J Pediatr Surg 36:1269, 2001. Castro E, Galambos C. Prox-1 and VEGFR3 antibodies are superior to D2-40 in identifying endothelial cells of lymphatic malformations-a proposal of a new immunohistochemical panel to differentiate lymphatic from other vascular malformations. Pediatr Dev Pathol 12:187,2009. Romani P, Shah A. Lymphangiomatosis and immunohistochemical analysis of four cases. Am J Surg Pathol 17:329,1993. Bliss DP, Coffin CM, Bower RJ, et al. Surgery 115:571,1994. Russo P. In Pathology of Pediatric Gastrointestinal and Liver Disease. Russo P, Ruchelli E, Piccoli DA (Ed.). Springer-Verlag, New York, 2004. Chapter 4, 87-8. Bruder E, Perez-Atayde A, Jundt G, et al. Vascular lesions of bone in children, adolescents, and young adults. Virchows Arch 454:161,2009. Gorham LW, Stout AP. Massive osteolysis (acute spontaneous absorption of bone phantom bone, disappearing bone); its relation to hemangiomatosis. J Bone Joint Surg Am 37:985,1955. Bruch-Gerharz D, Gerharz CD, Stege H, et al. Cutaneous vascular malformations in disappearing bone (Gorham-Stout) disease. JAMA 289:1479,2003. Moller G, Priemel M, Amling M, et al. J Bone Joint Surg Br 81-B,501,1999. Dorfman HD, Czerniak B. In Bone Tumors. St. Louis: Mosby, 1998. Chapter 13, Vascular Tumors, Pgs.759-61 Kawasaki K, Ito T, Tsuschiya T, et al. Virchows Arch 442:400,2003.