2014, Volume 30, Number 3, Page(s) 233-236
Pulmonary Lymphangioleiomyomatosis: A Rare Case
Yetkin AĞAÇKIRAN1, Arzu ERTÜRK2, Fatma İrem YEŞİLLER2, Nevin Taci HOCA2, Leyla Nesrin ÜSTÜN3, Nermin ÇAPAN2
1Department of Pathology, Atatürk Chest Diseases and Chest Surgery Training and Research Hospital , ANKARA, TURKEY
2Department of Chest Diseases, Atatürk Chest Diseases and Chest Surgery Training and Research Hospital , ANKARA, TURKEY
3Department of Chest Surgery, Atatürk Chest Diseases and Chest Surgery Training and Research Hospital , ANKARA, TURKEY
Keywords: Lymphangioleiomyomatosis, Immunohistochemistry, Lung neoplasms, Differential diagnosis
Lymphangioleiomyomatosis is an uncommon lung disease primarily
affecting women of childbearing age. It is characterized by the
progressive proliferation and infiltration of smooth muscle-like cells,
which lead to cystic destruction of the lung parenchyma; obstruction of
airways, blood vessels, and lymphatics; and loss of pulmonary function.
We present the case of a 46-year-old female patient with chest pain,
cough, sputum, and dyspnea on exertion for three weeks. Minimal
pneumothorax was noted, and the patient was referred to our center
for further investigation and treatment. High-resolution computed
tomography revealed numerous bilateral thin-walled air cysts and
interstitial thickening affecting the central and peripheral part of the
upper zone of the lung. We performed an open-lung biopsy to confirm
lymphangioleiomyomatosis. Our aim is to discuss the pathogenesis
and other lesions noted in the differential diagnosis of this rare disease.
Lymphangioleiomyomatosis (LAM) is an uncommon
lung disease primarily affecting women of childbearing
age. It is characterized by the progressive proliferation
and infiltration of smooth muscle-like cells (LAM
cells), which lead to the cystic destruction of the lung
parenchyma; obstruction of airways, blood vessels, and
lymphatics; and loss of pulmonary function1
. In 1966,
Cornog and Enterline first described what they termed
lymphangiomyoma; subsequent literature used different
. The coexpression of contractile proteins
and melanocytic markers with proliferating LAM cells
suggests it originates in perivascular epithelioid cells
(PECs). However, the definite origin of LAM cells is still
A 46-year-old female patient presented with cough, sputum persisting for a year, and dyspnea on exertion for three
weeks. The patient reported to the physician with cough,
and antibiotics were prescribed with no improvement
in symptoms. A chest CT taken at a later date revealed
minimal pneumothorax. She was referred to us for
further investigation and treatment. She was admitted
for differential diagnosis of minimal pneumothorax,
interstitial lung disease, and LAM. Routine tests were
conducted, and the pulmonary function test (PFT) revealed
FVC: 96%, FEV1: 68%, FEV1/FVC: 61%, and DLCO: 27%.
Nasal oxygen and bronchodilator treatment was started.
There was no α1-antitrypsin deficiency, and collagen
markers were negative. The thoracic surgery department
was consulted, oxygen treatment and follow-up with a PA
chest x-ray was suggested, and no chest tube was indicated.
High-resolution computed tomography (HRCT) revealed
numerous bilateral thin-walled air cysts and interstitial
thickening affecting the central and peripheral part of the upper zone of the lung (Figure 1
). An ultrasound of
the abdomen revealed a 6 x 2.5 cm lobulated contouredwalled
cystic lesion around the umbilicus in the right lower
paraaortic region. Past history of a subtotal hysterectomy
and left utero-salphingo-oopherectomy operation for
uterine leiomyoma in June 2010 was noted. Tumor markers
of the reproductive organs were negative, and transbronchial
biopsy with FOB was non-specific. A diagnostic open-lung
biopsy was performed.
Click Here to Zoom
|Figure 1: Thorax High-resolution computed tomography showing
a uniform multiple air cyst and interstitial thickening.
Macroscopically, the specimen from the left lower lobe was
4 x 2.5 x 1.5 cm and from the upper lobe was 4 x 1.8 x 1.5cm,
both with cystic features on the cut surface (Figure 2).
Click Here to Zoom
|Figure 2: Macroscopically, we notice diffuse cystic changes in the
On microscopic examination, proliferating LAM cells,
heterogeneous epithelioid and spindle-shaped immature
muscle-like proliferating cells, were found in the cystic space
of the lung parenchyma (Figure 3). An immunohistochemical
stain was positive for contractile proteins (smooth muscle
actin and desmin), the melanocytic marker HMB-45
(Figure 4), estrogen receptor (ER), progesterone receptor
(PR), and CD56 in the LAM cells. Pan cytokeratin, EMA,
CEA, S-100 protein, chromogranin, and CD34 stains were
negative. The Ki-67 proliferation index was 1%.
Click Here to Zoom
|Figure 3: Heterogeneous epithelioid and spindle-shaped immature
muscle-like proliferation cells in the cystic space of the lung
parenchyma (H&E; x200).
Click Here to Zoom
|Figure 4: The positive stain of HMB-45 prominent in the
epithelioid cells (immunoreactivity; x400).
The most frequently stated first clinical sign was spontaneous
pneumothorax (37.5%). Typically, LAM is a disease of
women of childbearing age and worsens during pregnancy
and following the administration of estrogens. The mean
age at disease onset is 38.9 years and at diagnosis 41.0 years.
The global prevalence of pulmonary LAM is unknown
and is estimated at approximately 1 to 5 of 106 women2
LAM occurs in two main forms: tuberous sclerosis complex
(TSC)-associated LAM and sporadic LAM (S-LAM). Most
LAM cases are sporadic, and S-LAM represents about 85%
of the patients. In these cases, there is no or little mutation
in the TSC1 or TSC2 gene, whereas in the sclerosis complex
(TSC) autosomal-dominant genetic disease, the TSC1 or
TSC2 gene is frequently affected. Compared to patients
with TSC1 mutations, patients with TSC2 mutations have
a higher cystic-formation rate2,4
The TSC1 gene is located on the long arm of chromosome
9 (9q34) and encodes the protein hamartin (130 kDa),
whereas TSC2 is located on the short arm of chromosome
16 (16p13.3) and encodes the protein tuberin (198 kDa)2-4. Mutations in TSC1 and TSC2 genes cause LAM cells to
exhibit features of coexpression contractile proteins (smooth
muscle actin and desmin) and melanocytic markers (HMB-
45, HMSA-1, Melan-A/MART-1). This suggests this lesion
should be considered a deficiency or dysfunction of the encoded proteins hamartin or tuberin, respectively, which
is believed to constitute activation of mTOR, leading to
increased protein translation and, ultimately, inappropriate
cellular proliferation, migration, and invasion2. LAM
cells are suggested to be of perivascular epithelioid cell
origin. However, the origin of LAM cells is still unclear. In
addition to contractile proteins and melanocytic markers,
there have been reports in the literature demonstrating
other positive markers such as CD1a2, CD63, PNL23,
cathepsin-k5, B7-H36, and the presence of estrogen receptor (ER) and progesterone receptor (PR) in 50% of
epithelioid LAM cells2.
In our case, during the differential diagnosis, we noticed
CD56 expression; so far, no studies in the literature have
examined this marker in LAM cases. A large series is
required to verify the reliability of this antibody. A study
of CD56 in soft tissue tumors revealed positivity in the
gastrointestinal and uterine smooth muscle cells but
negativity in the vascular smooth muscle cells and normal
skeletal striated muscle cells7.
Initially, LAM cells were believed to originate from
either the airway or vascular smooth muscle cells, but this hypothesis is not supported by the diffuse existence
of LAM cells throughout the lungs and the irregular
distribution within the nodules, without the formation
of organized layers. Another hypothesis—based on some
clinical, genetic, and cell culture studies—is that LAM
cells may originate from angiomyolipomas and be brought
into the lungs. However, about one-third of S-LAM cases
are without angiomyolipomas, and in such cases, LAM
cell origin cannot be explained by metastatic or neoplastic
cell dissemination. Another hypothesis about the origin
of LAM cells is that they begin as donor cells from a nonhost
source. The source of non-host cells could be an
organ donor, a blood transfusion, or fetal cells persisting in
maternal circulation. Evidence for the non-host cell theory
remains elusive1,2. Recent studies on angiolipomas, a
PEC-cell-associated group of tumors, showed positive
neural stem cell markers for NG2 and L1, suggesting these
cells (PECs) may originate from defective differentiating
precursor stem cells8. We believe a large LAM series
study on NG2 and L1 antibodies would enlighten us on
the histogenesis of the defective differentiating precursor
stem cells. Unfortunately, the origin of these cells is still
During the early stages of the disease, it is easy to misdiagnose
LAM cells that infiltrate as normal or emphysematous2.
Benign metastasizing leiomyoma is not usually associated
with cysts, and the nodules of smooth muscle are generally
larger than those seen in LAM. Patients always have a
history of uterine leiomyoma, and the smooth muscle cells
are negative for melanocytic markers, such as HMB-45 and
Melan-A9. Langerhans cell histiocytosis can present with
cyst formation radiographically; however, the predilection
of the small nodules or nodules with cystic changes in the
mid- and upper-lung zones and the infiltrating Langerhans
cell (positive for CD1a, S100, and langerin) and eosinophils
will differentiate it from LAM. Diffuse pulmonary
lymphangiomatosis shows diffuse proliferation of
lymphatic vascular spaces and smooth muscles, mimicking
LAM. The disease usually affects children of either sex
rather than women of childbearing age. Compared with
LAM, the smooth muscle proliferation is less marked,
without extension into the alveoli or cyst formation, and
is negative for HMB-45 staining. Minute pulmonary
meningothelial nodules are lesions histologically composed
of small nests of epithelioid meningothelial cells positive for
EMA but negative for HMB-452. In diffuse pulmonary
neuroendocrine cell hyperplasia, epithelial markers like
CEA and neuroendocrine markers like chromagranin are
positive10. In multifocal micronodular pneumocyte hyperplasia, EMA, cytokeratin, and surfactant apoprotein
A and B are positive, whilst HMB-45, smooth muscle actin,
desmin, CEA, ER, PR, and p53 are negative11,12.
Treatment of LAM involves several hormone-based
treatments, such as bilateral oophorectomy, gonadotropinreleasing
hormone agonists, tamoxifen, or progesterone.
Inhaled bronchodilator therapy may provide symptomatic
relief. Lung transplantation has been accepted as therapies
for end-stage pulmonary LAM. Novel macrolide agent
sirolimus (rapamycin), acting as an mTOR inhibitor,
has shown promising results in the treatment of LAM.
Other therapeutic targets—such as MMP inhibition
by an MMP inhibitor (doxycycline), Rhed GTPase
inhibition by 3-hydroxy-3-methylglutaryl-coenzyme A
inhibitors (statins), or JAK-STAT3 pathway inhibition by
interferon-γ—may also have potential for the treatment of
LAM13. We used hormone-based tamoxifen citrate 20
mg, administered twice daily, on our patient. The prognosis
of the disease varies. The five-year survival rate is between
50 and 97%.
We present this rare case to emphasize the pathogenesis
and the differential diagnosis of LAM, especially in the
early stage of the disease when lesions may be considered
normal or the result of emphysematous changes.
1) Krymskaya VP. Smooth muscle-like cells in pulmonary
lymphangioleiomyomatosis. Proc Am Thorac Soc. 2008;5:
2) Zhang X, Travis WD. Pulmonary lymphangioleiomyomatosis.
Arch Pathol Lab Med. 2010;134:1823-28.
3) Zhe X, Schuger L. Combined smooth muscle and melanocytic
differentiation in lymphangioleiomyomatosis. J Histochem
4) Nasir K, Ahmad A. Giant renal angiomyolipomas and pulmonary
lymphangiomyomatosis. Saudi J Kidney Dis Transpl. 2010;21:
5) Chilosi M, Pea M, Martignoni G, Brunelli M, Gobbo S,
Poletti V, Bonetti F. Cathepsin-k expression in pulmonary
lymphangioleiomyomatosis. Modern Pathology. 2009;22:161-6.
6) Boorjian SA, Sheinin Y, Crispen PL, Lohse CM, Leibovich BC,
Kwon ED. T-cell co-regulatory molecule expression in renal
angiomyolipoma and pulmonary lymphangioleiomyomatosis.
7) Miettinen M, Cupo W. Neural cell adhesion molecule distribution
in soft tissue tumors. Hum Pathol. 1993;24:62-6.
8) Lim SD, Stallcup W, Lefkove B, Govindarajan B, Au KS,
Northrup H, Lang D, Fisher DE, Patel A, Amin MB, Arbiser JL.
Expression of the neural stem cell markers NG and L1 in human
angiomyolipoma: Are angiomyolipomas neoplasms of stem cells?
Mol Med. 2007;13:160-5.
9) Kayser K, Zink S, Schneider T, Dienemann H, André S, Kaltner H,
Schüring MP, Zick Y, Gabius HJ. Benign metastasizing leimyoma
of the uterus: Documentation of clinical, immunohistochemical
and lectin-histochemical data of ten cases. Virchows Arch.
10) Coletta EN, Voss LR, Lima MS, Arakaki JS, Câmara J, D’Andretta
Neto C, Pereira CA. Diffuse idiopathic pulmonary neuroendocrine
cell hyperplasia accompanied by airflow obstruction. J Bras
11) Shintani Y, Ohta M, Iwasaki T, Ikeda N, Tomita E, Nagano T,
Kawahara K. A case of micronodular pneumocyte hyperplasia
diagnosed through surgical resection. Ann Thorac Cardiovasc
12) Kobashi Y, Sugiu T, Mouri K, Irei T, Nakata M, Oka M. Multifocal
micronodular pneumocyte hyperplasia associated with tuberous
sclerosis: Differentiation from multiple atypical adenomatous
hyperplasia. Jpn J Clin Oncol. 2008;38:451-4.
13) Lu SH, Hou YY, Tan YS, Xu JF, Zeng HY, Sujie AK, Wang
XD, Bai CX. Clinical and histopathological alterations of
lymphangioleiomyomatosis in 14 Chinese patients. Chinese
Medical Journal. 2009;122:1895-900.