Lung Biopsy Interpretation
Case 4 -
Anna-Luise A. Katzenstein & Jeffrey L. Myers
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
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.
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|
|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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