Complex Lymphatic Anomalies

Complex lymphatic Anomalies comprise several overlapping, yet distinct, clinical syndromes:

• Generalized Lymphatic Anomaly (GLA)
• Gorham-Stout Disease (GSD), and
• Kaposiform Lymphangiomatosis (KLA).

There is no significant incidence difference between males and females in any of these disorders, and all 3 disorders are so rare that it is difficult to establish true incidence.

Symptoms and History

All of these disorders tend to present with swelling (edema) of a localized area although generalized swelling is also possible. There are varying degrees of bone and soft tissue involvement seen in each of these disorders. Bone involvement can be severe enough to cause bone to dissolve/disappear (as in GSD see below), or to become weak enough to spontaneously break (fracture). Chylous effusions (accumulation of liquid made up of fat, water and lymphocytes) are frequently seen, and often there is spontaneous drainage either externally (leakage from the skin) or from one internal compartment to another. If the lung cavity or pericardial sack fills with fluid there can be significant problems with the function of these organs (resulting in shortness of breath and exercise intolerance). When the GI tract is involved there can be significant leakage of chylous fluid into the bowel which can cause problems with nutrition (from protein and fat loss) as well as diarrhea/bowel incontinence.

Diagnosis

As discussed above, the patient may present with swelling, pain, or leakage of fluid. The diagnosis is usually made with a combination of imaging and pathology.

Imaging. The most accurate imaging for the soft tissue components is MRI with contrast. Ultrasound can be used to define the fluid collections. An MR lymphangiogram is the optimal way to assess the lymphatic vessel system. Plain films and CT scans are the most useful for assessing bone involvement

Genetics. No specific genetic mutations have been found or inheritance patterns discovered for any of these disorders, but local gene errors were found to explain some of the symptoms (somatic mutations and mosaicism – e.g., PIK3CA)

Pathology. All three of these entities should stain positively for the lymphatic markers D2-40 and Prox1. The difference between the 3 disorders (despite significant overlap between them) is discussed below:

Kaposiform Lymphatic Anomaly (KLA) is the most aggressive and the rarest of these disorders. It is diagnosed at younger ages than the other two (often presenting in infants and toddlers though older ages are possible. Pleural effusions (lymphatic fluid accumulation around the lungs) have a higher incidence of hemorrhage. The diagnosis is made by biopsy material that stains positive for lymphatic markers (as above) but also shows the characteristic spindle cells that this diagnosis is defined by.

Generalized Lymphatic Anomaly (GLA) usually presents with a multi-centric proliferation of dilated lymphatic vessels similar to common Lymphatic Malformation (LM). The difference between Generalized Lymphatic Anomaly and LM is that Generalized Lymphatic Anomaly tends to affect multiple sites including many or all of the following: bone, liver, spleen, mediastinum (center of the chest), lungs, and soft tissues (including organs). Generalized Lymphatic Anomaly may be present at birth but usually becomes evident during the first 2 decades of life.

Gorham Stout Disease is rarer than Generalized Lymphatic Anomaly and although there may be soft tissue involvement, it is known for bone involvement where the bone cortex is specifically “dissolved”. Gorham Stout Disease bone lesions are usually adjacent to soft tissue masses that stain positively for lymphatic markers. One of the common names for GSD is “Vanishing Bone Disease”. Any bone can be involved but the most commonly involved are: ribs, cranium, clavicle and cervical bones, though hip, humerus and femurs are often described. Pain is usually from pathologic fractures (fractures that occur through the weakened bone), and the disease itself is often initially diagnosed when the patient is being investigated for a minor trauma which seems to be producing a major amount of pain or fracture. Of the 3 disorders, Gorham Stout Disease responds best to medical therapy with the treatments outlined below (which are also used for KLA and GLA), but complete cure is rare.

Treatment

• Sclerotherapy has been helpful where large cystic components exist
• Low fat diets are helpful to prevent accumulation of the fluid
• Higher protein diets can help replace the nutritional factors lost from the drainage
• Lymphatic massage, and compression garments are helpful for swollen limbs and to move the lymphatic fluid into a location where it can be more easily absorbed
• Medical therapy with Sirolimus and/or Interferon has been helpful in many cases
• Bone involvement can be ameliorated and sometimes reversed with Bisphophonates + Calcium and Vitamin D supplementation
• Where there are components of Lymphatic Conduction Disorder (lymphatic channels and cysts that are not connected with a drainage pathway leading to the venous system)—it is possible in some cases to surgically connect these areas to allow for better drainage