Case 4 -
Diffuse Pulmonary Lymphangiomatosis
Henry D. Tazelaar
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A 42 year old man presented with hemoptysis. He had a history
of bilateral pleural effusions and at one point in time had received a diagnosis of sclerosing
mediastinits. Two previous lung biopsies had shown pleural fibrosis. A bronchoscopy and pulmonary
angiogram failed to show a source of bleeding. While in the hospital he died and underwent a thorax only
autopsy. The submitting pathologist stated that both the pleura and pericardium were thickened.
Diffuse Pulmonary Lymphangiomatosis
This case represents one of the rare examples of what has
been called "diffuse pulmonary lymphangiomatosis" (DPL), a disease involving pulmonary lymphatics and
smooth muscle distinct from lymphangioleimyomatosis. Patients with DPL present from infancy to early
adulthood and this patient represents one of the oldest patients we have seen with this disorder.
Patients who present at a later age often have symptoms dating to childhood. The disease may be more
common in boys and men, but there are very few cases reported overall. Presenting signs and symptoms
include wheezing, recurrent pneumonia, "asthma", dyspnea, cough, and hemoptysis. Physical findings are
often normal, but some patients have a decrease in breath sounds, and crackles.
On chest radiograph, diffuse interstitial and alveolar infiltrates are generally identified, often
associated with pleural effusions. Computed tomographic (CT) findings include smooth thickening of the
intralobular septa and bronchovascular bundles, associated with patchy bilateral areas of ground glass
opacification. These findings may also be associated with bilateral pleural effusions, diffusely
increased attenuation of the mediastinal fat, and bilateral perihilar fullness. These latter two
findings indicate that mediastinal involvement may occur and likely led to the diagnosis of sclerosing
mediastinitis in this patient. Pulmonary function tests often show a mixed pattern with restriction
being the more prominent feature.
Although the high resolution CT scan has very characteristic, if not pathognomic, features, most
patients undergo biopsy for diagnosis. Histologically, these features are most notable at low power. As
exemplified by this case, the lungs show the presence of extensively anastomosing, variably sized,
endothelial-lined spaces diffusely distributed along lymphatic routes, i.e. in a subpleural, paraseptal,
perivascular, and peribronchiolar distribution. The spaces often contain acellular eosinophilic
proteinaceous-appearing material. Variably present along these lymphatic routes are asymmetrically
spaced bundles of spindly smooth muscle cells. Red blood cell-filled capillary spaces can occasionally
be found between the spindle cells and suggest a diagnosis of Kaposi's sarcoma. Distinctive mass lesions
or cysts of the type seen in lymphangioleiomyomatosis (LAM) are not present. The pulmonary parenchyma
may contain intra-alveolar hemosiderin-laden macrophages, small foci of intra-alveolar hemorrhage, and
sparse numbers of interstitial chronic inflammatory cells. Cells lining the spaces are positive for
Factor VIII related antigen or CD31, confirming their endothelial nature. The spindle cells are reactive
with antibodies to vimentin, desmin, actin, and progesterone receptor. They are negative for keratin and
HMB-45. Electron microscopy reveals the presence of elongated spindle cells with features of smooth
The disease is usually progressive and appears most aggressive in the youngest patients. Among the
nine reported patients in our series, two children died, one of pulmonary hemorrhage and the other after
heart-lung transplantation. Recent follow-up on the oldest patient in our series, a 33-year-old woman,
indicates that she died at age 35 of her lung disease. There are anecdotal reports of dramatic responses
The differential diagnosis for DPL includes lymphatic lesions of the lung, hemangiomatosis (including
pulmonary capillary hemangiomatosis), pulmonary involvement by Kaposi's sarcoma, and Kaposiform
At least four separate clinicopathologic categories of primary lymphatic lesions of the lung have been
identified including lymphangioma, LAM, lymphangiomatosis, and lymphangiectasis. The table shows a
pathologic classification of abnormalities for the lymphatic system which may help put cases of DPL in
Lymphangiomas are localized malformations thought to arise from sequestered lymphatics that fail to
communicate normally with the lymphatic system. They have some ability to grow as they accumulate large
amounts of fluid. Lymphangiomas should not generally be difficult to distinguish from DPL. They produce
symptoms by mass effects and because of their tendency to be associated with effusions. Lymphangiomas
are most common in the head and neck region and on the extremities, although they have been reported to
occur in the lungs. In contrast to DPL, lymphangiomas can often be removed in their entirety, and their
complete removal generally results in cure. Although histologically the lymphatic spaces in
lymphangiomas can be variable in size and contain a component of smooth muscle, their lack of
distribution along lymphatic routes should help to separate them from DPL.
Although some cases of DPL have probably been reported as pulmonary lymphangiectasis, the latter is
characterized by dilatation of pre-existing lymphatics (hence they also occur along lymphatic routes).
This sometimes results in macroscopically visible spaces. Most cases occur in infants and young
children, although older patients have been reported. Lymphangiectasis can affect one lobe or the entire
lung, and the walls of the spaces may contain small amounts of smooth muscle, particularly in secondary
cases. The distinction between lymphangiectasis and DPL should be made on the basis of the size and
number of participating lymphatic spaces. In DPL, the spaces tend to be smaller and more numerous and
the smooth muscle component more pronounced.
Table. Pathologic Classification of Abnormalitiesof the Lymphatic System*
but isolated predominantly to one organ
involving different organ systems, including bone
||Limited to the lungs
||With lung and mediastinal
with intestinal involvement
to obstruction or pulmonary venous hypertension
and angiomatous lesions
of lymphatic and other tissues
* from Pediatr 1990; 86:988 and Hum Pathol 1993; 24:1320
The pathologic changes in LAM are not limited to pre-existing lymphatic spaces and routes, and the
changes are most marked within the alveolar parenchyma. While the proliferation of smooth muscle cells
in LAM may surround and infiltrate arterioles, venules, and lymphatics, the cystic airspace enlargement
involving the alveoli is the most prominent and diagnostic feature. The cysts are surrounded by a
collarette of smooth muscle cells. The more dispersed pattern of involvement and the relative greater
proportion of smooth muscle in LAM should also aid in the differential diagnosis. Additionally, the
character of the smooth muscle bundles in LAM is somewhat different from that in DPL. In LAM, it tends
to be "immature" and more haphazardly arranged while in DPL it tends to be present in parallel arrays and
the nuclei tend to be more blunt-ended and cigar-shaped. Staining for HMB-45, a characteristic feature
of LAM has not been reported in cases of DPL. The presentation in women primarily in the reproductive
age group and the radiologic features can also help to differentiate LAM from DPL in some cases.
The distinction of DPL from hemangiomatosis may be more difficult and rests primarily on the absence
of blood in the vascular spaces. In some cases, it may be impossible to make this histologic separation,
and it is possible that some cases of hemangiomatosis represent cases of DPL or vice versa.
Pulmonary capillary hemangiomatosis is a disorder associated with pulmonary hypertension and caused by
the proliferation of multiple thin-walled vascular spaces (capillaries) in the pulmonary interstitium,
without a predilection for lymphatic routes. A smooth muscle component has not been described in this
disorder. These features, as well its occurrence in an older mean age group should allow for ready
distinction from DPL.
Compared to Kaposi's sarcoma, the spindle cells in DPL tend to be less compact and are associated with
larger vascular spaces. In addition, the nuclei of the spindle cells in DPL tend to be less elongated,
less hyperchromatic, and have blunted ends like normal smooth muscle cells. Finally, DPL lacks the PAS
positive globules characteristic of Kaposi's sarcoma.
One final entity that also deserves attention as a possible source of confusion with DPL is the
Kaposiform hemangioendothelioma (KH) of infancy and childhood. Not only did one of the reported cases
involve the chest wall, but this lesion also appears to occur in patients and tissues with generalized
lymphangiomatosis, as well as the Kasabach-Merritt syndrome. Although the spindle cells in KH bear some
morphologic resemblance to the small plaque-like collections of smooth muscle cells of DPL, the solid
growth pattern, immunostaining profile (actin negative, CD34 positive), and electron microscopic features
of the cells in KH indicate their vascular rather than smooth muscle character.
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