Introduction

Lymphangioleiomyomatosis (LAM) is a systemic and progressive disease in which tumor cells called smooth muscle-like LAM cells slowly increase in the lungs, lymph nodes, kidneys, etc. The LAM is a rare disease that predominantly affects women of childbearing age, with a prevalence of 1.9–4.5 per million in Japan (1). Loss of the function of tuberous sclerosis complex 1 or 2 (TSC1 or TSC2), the genes responsible for tuberous sclerosis, and tumor suppressor genes, causes abnormal activation of the mammalian target of the rapamycin (mTOR) pathway, resulting in cell proliferation, migration, and invasion. Subjective symptoms may include shortness of breath on exertion, cough, wheezing, chest pain and dyspnea due to a pneumothorax. Although there is currently no curative treatment, obstructive pulmonary dysfunction is treated with medications such as bronchodilators. Pneumothorax and pleural effusion are treated with drainage and pleurodesis; lung transplantation is involved in severe cases (2, 3). Previous studies have reported pathological and molecular similarities between LAM and breast cancer (4, 5), and cohort studies of LAM have reported a high prevalence of breast cancer (6, 7). However, there is limited evidence regarding the safety of postoperative whole breast irradiation following partial mastectomy for breast cancer patients who exhibit abnormal pulmonary findings due to LAM.　Here we report three cases of patients who received breast conservation therapy for breast cancer with LAM.

Case reports

Case 1

A 40-year-old premenopausal woman brought by ambulance complaining of shortness of breath and back pain. Chest X-rays showed pneumothorax. Chest computed tomography (CT) images showed numerous thin- walls cysts within the lungs and enhanced masses in the boundary between the upper outer and upper inner quadrants of the left breast (Fig. 1 A, B). Contrast-enhanced CT of the pelvic region revealed a retroperitoneal cystic lesion consistent with LAM (Fig. 1 C). The biopsy of the breast tumor revealed invasive ductal carcinoma. The patient had received pleurodesis for pleural effusion and drainage for pneumothorax, and was suspected of LAM due to a medical history and imaging findings. She was referred to our hospital for further evaluation and treatment of breast cancer and LAM.

The patient had a previous history of chylothorax and chest effusion at 31 years of age, and was hospitalized for pneumothorax at 34 with leiomyoma of the uterus.

She was diagnosed with cT2N0 breast cancer. She underwent left partial mastectomy and sentinel lymph node biopsy followed by axillary lymph node dissection, since sentinel lymph node biopsy showed positive lymph node.

Histologically, the tumor was a invasive ductal carcinoma with 2.3 cm maximum size and clear margins. Dissected axillary lymph nodes showed breast cancer metastasis and spindle-shaped cells associated with LAM, in which immunostaining for ER-positive, αSMA, desimin-positive, and was partially positive for HMB-45. The stage was determined to be pT2pN1mi M0 (Stage IIB). The immunohistochemical examination revealed that the tumor was ER (+), PgR (+), and Her2 Neu (-) with a Ki-67 index of 12.6%. Postoperative hormone therapy (LH-RH analogue, Tamoxifen) was initiated and referred to our department for whole breast irradiation. The patient received adjuvant radiation of the left breast with 50Gy in 20 fractions (5 weeks). Radiation dermatitis G1 was observed as an acute adverse event. Fever was observed during the radiotherapy, but a causal relationship between irradiation and fever was considered negative because the fever was repeated from before the start of the radiotherapy. No radiation pneumonitis was observed during the course, and the follow-up period. The use of sirolimus was considered for LAM, but it was not used because it was complicated by the presence of a malignant tumor, and it is under observation. An LH-RH analogue was administered for 5 years and tamoxifen for 10 years. At 146 months of the follow-up, the patient is alive without any recurrence or metastasis of breast cancer or progression of LAM.

Case 2

A 51-year-old premenopausal woman diagnosed with polycystic lesions of the lungs on CT after thyroid tumor surgery was suspected of LAM and referred to our hospital for further evaluation and treatment. A CT scan of the whole body showed an 18×16 mm mass in the lower outer quadrant of the right breast, and the patient was referred for breast surgery. The diagnosis was of invasive ductal carcinoma by echo-guided mammotome biopsy. She was diagnosed with cT2N0 breast cancer. The patient underwent partial right mastectomy and sentinel lymph node biopsy. Histologically, the tumor was an invasive ductal carcinoma with 27 ×21 mm size and clear margins. The sentinel lymph node biopsy was negative. The stage was determined to be pT2pN0 M0 (pStage ⅡA). Immunohistochemical examination revealed the tumor as ER (+), PgR(+), and Her2 Neu (-) with a Ki-67 index of 48.1%. The patient received adjuvant chemotherapy (docetaxel and cyclophosphamide 4 cycle). After completion of the chemotherapy, administration of tamoxifen was started, and the patient was introduced to the department of radiation oncology for postoperative irradiation. She received adjuvant radiation of the right breast with 45Gy in 18 fractions (4.5 weeks). The CT, which was taken three months after completion of radiotherapy showed an increase in concentration and contractility changes in the middle lobe of the right lung (Fig. 2). She was diagnosed with radiation pneumonitis G1 in the absence of subjective symptoms such as fever and cough continued tamoxifen for 92 months until menopause was confirmed, and then switched to letrozole after the menopause. At 96 months of follow-up, she is alive without any recurrence or metastasis of breast cancer or progression of LAM.

Case 3.

A 56-year-old postmenopausal woman was referred to our hospital because of increased calcification on mammography. The patient had been screened for breast cancer once a year. She had a previous history of pneumothorax nine years ago and was diagnosed with LAM by thoracoscopic biopsy and was under observation. She was diagnosed with cT1N0 breast cancer and subsequently underwent a lumpectomy and sentinel lymph node biopsy. Histologically, the tumor was an invasive ductal carcinoma, with a 10×4.5 mm size and clear margins. The sentinel lymph node biopsy was negative. The stage was determined to be pT1bpN0 M0 (pStage ⅠA). The immunohistochemical examination revealed that the tumor was ER (+), PgR(+), and Her2 Neu (-) with a Ki-67 index of 12.0%. Postoperative letrozole is initiated and she was referred to our department for postoperative irradiation, also KPS 90% with no respiratory symptoms. She received adjuvant radiation of the left breast with 45Gy in 18 fractions (4.5 weeks). Early adverse events of dermatitis G1 were observed. No radiation pneumonitis was observed during and after the radiation therapy. She continued letrozole administration for 60 months. At 67 months of follow-up, she is alive without any recurrence or metastasis of breast cancer or progression of LAM.

Discussion

We report three cases of breast cancer with LAM. All received breast conservation surgery followed by whole breast radiotherapy without serious adverse effect. After the radiotherapy, hormone therapy was continued, and they are alive without any recurrence of breast cancer or progression of LAM during the follow up.

The LAM is a systemic disease, particularly known to cause chest lesions. All three patients had chest lesions but there were no serious adverse pulmonary events due to radiation therapy for the affected breast. Kelly et al. reported a patient diagnosed as LAM and subsequently with metastatic breast cancer who received chemotherapy (8). To our knowledge, there are no previous reports of radiation therapy to the chest for patients affected by LAM.

A previous epidemiological study using LAM country cohorts revealed breast cancer standardized incidence ratios of ≧ 2.25 for all cohorts and ≧ 4.88 for the pre-menopausal age group (women younger than 50) (6). Nunez et al. reported that breast cancer associated with LAM is frequently observed in premenopausal women and is typically characterized by hormone receptor positivity (6, 7). In this study, two of the three cases were premenopausal and all three were hormone receptor positive, consistent with previous reports.

Several studies suggest that LAM and breast cancer may share a common pathophysiology.

Jiang et al. (9) have shown that low expression of hamartin and tuberin, which are the products of TSC1 and TSC2, in breast cancer has a poor clinical prognosis.

Geribay et al. have reported that LAM biomarkers are associated with lung metastasis and cell stemness in breast cancer (4). Yang et al. utilized bioinformatics approaches to analyze LAM and estrogen receptor (ER)-positive breast cancer, demonstrating that there are several genes commonly expressed for the two conditions (5). These findings suggest a potential shared pathophysiological mechanism underlying LAM and ER-positive breast cancer.

Previous studies have suggested that estrogen is involved in the pathogenesis of LAM, and that LAM is considered to result from aberrant activation of the mTOR signaling pathway, caused by functional defects in the tumor suppressor genes TSC1 and TSC2 (2). This dysregulation promotes abnormal cell proliferation and migration. Furthermore, as the mTOR pathway is known to be activated by estrogen, elevated estrogen levels are believed to contribute to both the initiation and progression of LAM. Estrogen-altering events like menstruation, pregnancy, and exogenous estrogen treatment can trigger or exacerbate LAM symptoms (10).

The efficacy of hormonal therapy for LAM has not been established (11) and its use is not currently recommended (12). In the present case series, all three patients received hormonal therapy as part of the breast cancer treatment; notably, none of the patients experienced recurrence of breast cancer or progression of LAM during the follow-up period.

Conclusions

We report three cases of breast cancer with LAM, all of which received breast-conserving therapy. All cases were able to receive standard therapy and demonstrated favorable clinical courses, with no recurrence of breast cancer or progression of LAM observed during the long follow-up period.