Case 4 -

Diffuse Pulmonary Lymphangiomatosis Henry D. Tazelaar Mayo Clinic Arizona

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History 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. Case 4 - Figure 1 - Low power of bronchus with anastomosing vascular spaces. Case 4 - Figure 2 - Medium power of bronchial wall and adjacent lung with spongy vascularity. Case 4 - Figure 3 - Medium power highlighting compact spindle cells along spaces. Case 4 - Figure 4 - Compact spindle cells with bland elongate nuclei. Case 4 - Figure 5 - Actin stain. Diagnosis Diffuse Pulmonary Lymphangiomatosis Discussion 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 muscle cells. 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 to alpha-interferon. The differential diagnosis for DPL includes lymphatic lesions of the lung, hemangiomatosis (including pulmonary capillary hemangiomatosis), pulmonary involvement by Kaposi's sarcoma, and Kaposiform hemangioendothelioma. 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 perspective. 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* Lymphangiomas          Lymphangioma simplex        Cavernous lymphangioma        Cystic lymphangioma (cystic hygroma)     Lymphangiomatosis          Multifocal, but isolated predominantly to one organ        Generalized, involving different organ systems, including bone     Lymphangiectasia          Primary (congenital)           Thoracic            Limited to the lungs          With lung and mediastinal involvement       Generalized, with intestinal involvement      Secondary, due to obstruction or pulmonary venous hypertension     Lymphangiosarcoma       Lymphedema       Mixed lymphatic and angiomatous lesions       Combinations of lymphatic and other tissues          Lymphangiomyoma (localized)        Lymphangioleiomyomatosis         Lymphangiolipoma     * 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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