Case 3a -
Children's Hospital Boston
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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.
1. Lymphatic malformation
2. Venous malformation
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.
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.  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. 
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.  In extensive or generalized lesions, abnormalities of large lymphatic trunks
including the thoracic duct, such as ectasia, lack of valves or atresia, have been
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.  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. 
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.  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.  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. 
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.  In Gorham-Stout syndrome, also known as "disappearing bone disease" and
"phantom bone disease",  one or more axial or long bones, often contiguous, gradually
demineralize and "disappear". In our experience and that of others,  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.  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.
Late lesions show fibrous tissue of bone. 
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