—  SHORT COURSE #26  —

Lung Biopsy Interpretation

Case 4 - Lymphangioleiomyomatosis (LAM)

Anna-Luise A. Katzenstein & Jeffrey L. Myers


Clinical History
This 52 year old woman was admitted for orthotopic right lung allotransplantation. Her respiratory problems began at the age of 36 years when she developed recurrent spontaneous pneumothoraces. About three years after experiencing her first pneumothorax she underwent sequential left and right parietal pleurectomies. She suffered no pneumothoraces after surgery, but experienced progressive shortness of breath and a steady decline in exercise tolerance. She underwent transplantation for presumed idiopathic bullous emphysema.

Microscopic Description:


Case 4 - Figure 1 - Low magnification photomicrograph demonstrating cystic space associated with nodular aggregates of spindle cells.
Case 4 - Figure 2 - Higher magnification view highlighting the nodular aggregate of spindle cells. The cells are haphazardly arranged in the wall of the cystic space and surround vascular spaces.
Case 4 - Figure 3 - High magnification view showing plump spindle cells with cytologic attributes resembling smooth muscle cells.

The main change in sections from the explanted lung is the present of prominent cystic spaces. On closer inspection, many of the cystic spaces are associated with expansion of alveolar septa by blunt spindle cells with cytologic features typical of smooth muscle cells. The spindle cells are arranged in compact bundles that are present not only within alveolar septa comprising the cyst walls, but also around distal airways and blood vessels. There is associated hemosiderin pigment, attesting to the effects of blood vessel involvement.

Discussion
Lymphangioleiomyomatosis (LAM), also called lymphangiomyomatosis, is a rare condition that affects women almost exclusively, usually in the reproductive age group. The classic clinical triad is diffuse interstitial lung disease, recurrent pneumothoraces, and chylous pleural effusions. Hemoptysis is also a common presenting complaint. Physiologic testing demonstrates airflow obstruction with air trapping associated with disproportionately severe hypoxemia and reduction in DLCO. Chest radiographs are normal early in the course of the illness, but eventually show diffuse interstitial opacities, cystic spaces resembling honeycomb change, and paradoxical lung enlargement. This constellation of findings is said to be pathognomonic of this condition. High resolution CT scans show characteristic changes and can be extremely useful in diagnosis. LAM traditionally has been considered a relentlessly progressive disorder with a poor prognosis. A review of 32 patients reported from the Mayo Clinic by Taylor and colleagues suggested that as many as 80% of patients may survive for ten years or more, with most respiratory deaths occurring within five years of diagnosis. A recent analysis of a large number of French patients showed similar survival rates. Others report a less favorable prognosis. Progestogen therapy has proven most effective in treating this condition, although various other hormonal manipulations have been attempted with varying degrees of success. LAM is also an indication for lung transplantation, but can recur in lung allografts.

LAM is related to tuberous sclerosis complex (TSC), a multisystem autosomal dominant disorder characterized by the presence of hamartomatous tumors in various organs, most commonly skin, brain, heart and kidney. About 1-3% of patient with TSC have lung involvement that is morphologically indistinguishable from sporadically occurring LAM. Patients with TSC and LAM are interesting in that they tend to be women of reproductive age without CNS stigmata of TSC and thus resemble other patients with LAM. The single exception is a recently reported example of LAM in a man with underlying TSC. A recent report suggests that as many as 28% of women with TSC may have pulmonary LAM. Renal angiomyolipomas, common tumors in patients with TSC, are seen in nearly 60% of patients with otherwise sporadic LAM. Recent observations suggest that there may be common genetic events in LAM and the other hamartomatous and neoplastic manifestations of TSC.

The main pathologic abnormality in LAM is a disorderly proliferation of specialized smooth muscle cells along lymphatic pathways with extension into bronchiole walls, veins, and small air spaces. The proliferating cells tend to be spindled in shape, although plump epithelioid forms also occur and can predominate in some cases. Spindle and epithelioid cells frequently coalesce to form nodules. Cystic "emphysematous" spaces are common especially in advanced disease, and usually contain smooth muscle bundles within at least a portion of their walls. The presence of these cystic spaces may be the first clue to the diagnosis at low magnification. Hemosiderin often is present within surrounding air spaces and attests to pulmonary hemorrhage in these patients.

Micronodular pneumocyte hyperplasia (MNPH) is another manifestation of lung disease in patients with underlying TSC or sporadically occurring LAM. MNPH comprises circumscribed proliferations of cytologically bland type 2 pneumocytes in a pattern resembling bronchioloalveolar adenocarcinoma. Popper and colleagues coined the term MNPH to call attention to this epithelial proliferation involving the lungs of a 38 year old woman with TSC and LAM. Spencer and subsequently Corrin and colleagues had previously illustrated identical lesions in patients with TSC and LAM, respectively. More recently Muir et al. reported a series of 14 patients with MNPH, including nearly all previously reported examples. Ten (71.4%) of their patients, all women, had associated LAM and seven of these had other manifestations of TSC. Two additional patients had TSC without evidence of LAM, including one man (24 years of age). Two patients had MNPH as an isolated finding without TSC or LAM, and one of these was also a man (57 years of age). The recently reported example of LAM in a man with underlying TSC was also associated with MNPH. Indeed the combination of LAM and MNPH in a lung biopsy should be viewed as strong evidence in support of a diagnosis of TSC in a patient of either gender.

The modified smooth muscle cells of LAM are likely derived from perivascular epithelioid cells. Immunostaining results have shown features consistent with smooth muscle differentiation, including consistent expression of sex steroid receptors. Perhaps the most distinctive and compelling feature of the specialized smooth muscle cells in LAM is consistent expression of melanogenesis-associated proteins, most commonly HMB45. Melan-A is a less sensitive marker for this condition. HMB45 can be a helpful diagnostic marker in difficult cases such as small transbronchial biopsies. A subset of LAM cells are positive with antibodies for matrix metalloproteinases and their activators indicating that these may play a role on the elastic fiber degradation that contributes to the cystic change. Recent immunohistochemical studies using confocal microscopy suggest that there may be immunophenotypically distinct populations of small spindle cells and larger epithelioid cells as summarized in the table. This dimorphic population of lesional cells is not usually apparent in routine histologic preparations, and the significance of these observations is uncertain. With the exceptions of smooth muscle actin and HMB-45, frequency of immunoreactivity is diminished after hormonal treatment.

Table 1: Immunophenotype of putative cell subsets in LAM

Antigen Epithelioid cells Spindle cells Immunoreactivity diminished after treatment?
SMActin + + No
HMB45 + - No
ER/PR + - Yes
PCNA Yes
MMP-2 + + ?*
MT-1-MMP - + Yes

* immunostains with mouse monoclonal (Vs. rabbit polyclonal) diminished with treatment

The differential diagnosis of LAM is limited. So-called benign metastasizing leiomyoma is a rare condition characterized by the presence of multiple circumscribed nodules of cytologically bland smooth muscle cells within the lungs. The nodules differ from the lesions of LAM in that they are usually solid and well circumscribed, and frequently have a "biphasic" appearance due to the presence of entrapped alveolar epithelial cells. Hemosiderin pigment deposition can be a prominent feature of LAM and may lead to confusion with pulmonary hemorrhage syndromes, particularly idiopathic pulmonary hemosiderosis. The presence of cystic spaces coupled with foci of neoplastic spindled cells in LAM should serve to distinguish these conditions.

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