Author's response to reviews Title: Solitary Pulmonary Nodule of Benign Metastasizing Leiomyoma associated with Primary Lung Cancer: a case report Authors:

Introduction: Benign metastasizing leiomyoma in the lung is a very rare disease characterized by the growth of uterine leiomyoma tissue. In most cases there is a previous history of hysterectomy for uterine leiomyoma. Case presentation: A 50-year-old Asian woman underwent total abdominal hysterectomy for uterine leiomyoma at the age of 37 years old. She was referred to our hospital because of sudden anterior chest pain. Chest CT scan revealed a ground-glass opacity (GGO) in the left bronchial segment S10, and a solitary small nodule in the left S4. We performed a left lower lobectomy and an upper lung partial resection in order to make a definitive diagnosis and for further therapeutic strategy plan. The GGO in the left S10 was a primary lung adenocarcinoma, while the small nodule in the left S4 was diagnosed as a benign metastasizing leiomyoma (BML). No additional therapy was done and, the patient was followed up by chest CT scan. Up to date, repetitive evaluation by chest CT scan showed no sign of BML or lung cancer recurrence. Conclusion: This is a very rare case of benign metastasizing leiomyoma of the lung associated with primary lung cancer. This comorbid association should be considered in the differential diagnosis when a lung solitary nodule is detected in a patient with a history of uterine leiomyoma. Introduction Benign metastasizing leiomyoma (BML) is a very rare disease characterized by the growth of uterine leiomyoma tissue in the lung (1). In most cases there is a previous history of hysterectomy for uterine leiomyoma; however, the pathogenesis of the disease has not been as yet elucidated. The comorbid association of primary lung cancer and BML is even more uncommon. Here, we report a case of BML associated with primary lung cancer. Case Presentation The patient was a 50-year-old Asian woman that had undergone total abdominal hysterectomy for uterine leiomyoma at the age of 37 years old. She was non-smoker and her alcohol intake was only social. She was referred to our hospital because of sudden anterior chest pain. Hematology, biochemistry and blood gas analysis were normal. Chest CT scan revealed a ground-glass opacity (GGO) in the left S10 lung segment (Figure 1A) with 1.3 cm in size, and a solitary small nodule of 5 mm in diameter localized in the left S4 segment (Figure 1B). From the beginning, we suspected lung carcinoma, but we could not get the patient’s consent for performing bronchoscopic examination and surgical resection. Follow-up with CT showed that the GGO size slightly increased and that small nodule size had not changed. We suspected that GGO was lung carcinoma, but it was difficult to rule out whether the small nodule was lung metastasis. If this small nodule was not lung metastasis, the lung carcinoma could have been considered as being in early stage. We considered that pathological examination by surgical resection was appropriate because it was also an approach for treating the lung carcinoma. We performed a left lower lobectomy and an upper lung partial resection in order to make a definitive diagnosis and to decide further therapeutic strategies. The pathological diagnosis of the GGO in the left S10 was primary lung adenocarcinoma (localized bronchioloalveolar carcinoma)(Figure 2). On the other hand, pathological examination of the small nodule in the left S4 showed spindle-shaped smooth muscle cells and low cuboidal metaplastic bronchiolar epithelia surrounded by fascicles of smooth muscle cells without mitosis and nuclear atypia (Figure 3A). Immunohistochemical staining of thyroid transcription factor-1(TTF-1) and surfactant apoprotein A(SP-A) showed epithelial structures composed of alveoli or bronchioli (Figure 3B, 3C), suggesting that the low cuboidal metaplastic bronchiolar epithelium derived from the pre-existing bronchiolar epithelium. There was positive immunohistochemical staining for α-smooth muscle actin (α-SMA) and spindle-shaped cells (Figure 3D), suggesting that spindle-shaped cells were smooth muscle cells. Positive immunoreactivity for estrogen receptor(ER) and progesterone receptor(PgR), suggests that the spindle-shaped cells were uterine smooth muscle cells (Figure 3E, 3F). Unfortunately, histological sample of the uterine leiomyoma was not available for comparison. The small nodule was diagnosed BML based on the results of immunohistochemical staining and the past history of uterine leiomyoma. No additional therapy was done and follow-up of the patient by chest CT scan was continued. During four years of follow-up, no recurrence of either BML or lung cancer could be detected. Discussion Benign metastasizing leiomyoma (BML) is a disease in which a tissue from benign uterine leiomyoma is detected as a solitary nodule or as multiple nodules in the lungs of patients with a previous history of hysterectomy for uterine leiomyoma. In 1939, Steiner et al(1) reported for the first time BML as metastasizing fibroleiomyoma of the uterus, and since then there have been several similar reports. Abramson et al (2) reported that the average age of patients with BML is forty-eight, that the period from hysterectomy to nodule discovery is variable from three months to twenty-six years and that the first symptom of BML is almost nothing or sometimes cough or chest pain. Horstmann et al (3) reported that the radiological presentation of BML can be as multiple nodules in 87% of cases (bilateral nodules, 70% and unilateral nodule, 17%) or as a solitary nodule in 13%. The main metastatic site of BML is the lung but other sites including lymph nodes, soft tissue of the pelvis, bone, bone marrow, greater omentum, peritoneum, and heart have been also reported (4). Tsunoda et al (5) reported only one case of benign metastasizing leiomyoma of the lung complicated with primary lung cancer. There is no case in the literature about the association between lung cancer and BML other than this report. Thus, we believe that this is a very rare case of BML associated with primary lung cancer. Recent studies have shown that BML is caused by lung metastasis of uterine leiomyoma, which is histologically a benign tumor with very low grade of malignancy; this latter has been reported to depend on sex hormones (1,6,7,8 ). On the other hand, Patton KT et al have previously reported that BML results from the monoclonal, hematogenous spread of an apparently benign uterine leiomyoma (9). However, these conclusions are still controversial. Pathological examination of BML showed spindle-shaped cells without mitotic activity or nuclear atypia surrounded by cuboidal bronchiolar epithelial cells; additional immunohistochemical stainings showed that the spindle-shaped cells derived fromsmooth muscle cells of the uterus, and that the low cuboidal metaplastic cells derivefrom pre-existing bronchial cells (4). The presence of TTF-1 is usually assessed toconfirm the diagnosis of primary non-small cell lung carcinoma (speciallyadenocarcinoma) (10); but the purpose of TTF-1 staining in our particular case was todecide whether the low cuboidal metaplastic bronchiolar epithelium observed in thepathological specimens derived from the pre-existing bronchiolar epithelium because itis known that TTF-1 is only expressed on the normal epithelium of lung and thyroid (10).We believe that the diagnosis of BML is not dependent on the expression of TTF-1.Pathological comparison between the solitary pulmonary nodule and the originaluterine tumor should provide confirmatory evidence but the sample was not available.However, the small lung nodule was diagnosed as BML based on the results of theimmunohistochemical staining and the past history of hysterectomy for uterineleiomyoma.There is no standard therapy for BML. Recently, Patton KT et al (9) suggested thepossibility of hormonal treatment for BML with positive immunoreactivity for ER andPgR. Other studies have shown improvement of BML after ovariectomy, administrationof progesterone or Gn-RH agonist and menopause (11). The prognosis of the disease isalso unclear. In the present reported case, although the pathological stage of lungcarcinoma was stageIA, we considered that CT follow-up was necessary at intervals of3 to 6 months including follow-up of BML recurrence. No additional therapy was doneand the follow-up by chest CT scan showed no recurrence of BML or lung cancer.ConclusionWe reported a very rare case of BML associated with primary lung cancer. Thiscomorbid association should be considered in the differential diagnosis when a lungsolitary nodule is detected in a patient with a history of uterine leiomyoma.ConsentWritten informed consent was obtained from the patient for publication of this casereport and any accompanying images. A copy of the written consent is available forreview by the Editor-in-Chief of this journal.Competing interestsThe authors declare that they have no competing interests.Authors’ contributionsNT wrote the manuscript. TK was responsible for the manuscript concept and finalcorrections to the manuscript. ECG, YT, MY and OT supervised this patient care andmanuscript. KF, MO, AF, TT and HK were participated in patient care as a team. All authors have read and approved the final manuscript.References1. Steiner PE: Metastasizing fibroleiomyoma of the uterus. Am J Pathology.1939,15 :89-109.2. Abramson S, Gilkeson RC, Goldstein JD, Woodard PK,Eisenberg R, Abramson N:Benign metastasizing leiomyoma:clinical, imaging, and pathologic correlation. Am JRoentgenol. 2001,176:1409-1413.3. Horstmann JP, Pietra GG, Harman JA,Cole NG, Grinspan S: Spontaneousregression of pulmonary leiomyomas during pregnancy. Cancer . 1977,39:314-321.4. Rivera JA, Christopoulos S, Small D, Trifiro M: Hormonal manipulation of benignmetastasizing leiomyomas : report of two cases and review of the literature. J ClinEndocrinol Metab. 2004,89:3183-3188.5. Tsunoda Y, Tanaka K, Hagiwara M: A case of benign metastasizing leiomyoma ofthe lung complicated with primary lung cancer. Japanese Journal of Lung Cancer .2009,49: 445-449.6. Wolff M, Silva F, Kaye G: Pulmonary metastases (with admixed epithelial elements)from smooth muscle neoplasms. Report of nine cases, including three males. Am JSurg Pathol. 1979,3:325-342.7. Groeneveld AB, Bosma A, Ceelen TL, Kouwenhoven TJ, Meuwissen SG: Progressiveand fatal course of a patient with a multifocal leiomyomatous tumor. Am JGastroenterol. .1986,81:702-707.8. Banner AS, Carrington CB, Emory WB, Kittle F, Leonard G, Ringus J, Taylor P,Addington WW: Efficacy of oophorectomy in lymphangioleiomyomatosis and benignmetastasizing leiomyoma. N Engl J Med. 1981,305:204-209.9. Patton KT, Cheng L, Papavero V: Benign metastasizing leiomyoma: clonality,telomere length and clinicopathologic analysis. Modern Pathology. 2006,19:130-140.10. Yatabe Y, Mitsudomi T, Takahashi T: TTF-1 expression in pulmonaryadenocarcinomas. Am J Surg Pathol. 2002,26:767-773.11. Rakhshani N, Hormazdi M, Abolhasani M, Shahzadi M: Benign metastasizingleiomyoma of the uterus. Arch Iran Med. 2007,10:97-99. Figure LegendsFigure 1. Computed tomography (CT) scan of the chest on admission to our hospital.(A) Chest CT scan shows ground-glass opacity (arrow) in the left S10 lung segment(GGO) of 1.3 cm in size. (B) Chest CT scan shows a solitary small nodule (arrow) of 5mm in diameter in the left S4 segment.Figure 2. Histopathology of the lung tumor in the left S10.Pathological examination of the GGO in the left S10 depicts a localizedbronchioloalveolar carcinoma( H&E; staining, x400).Figure 3. Histopathology of the lung tumor in the left S4.(A) Pathological examination of the lung small nodule in the left S4 segment revealsthat the tumor is composed of spindle-shaped smooth muscle cells and a low cuboidalmetaplastic bronchiolar epithelium surrounded by fascicles of smooth muscle cellswithout mitosis or nuclear atypia ( H&E; staining, x400).(B) Immunohistochemical staining of TTF-1 shows positive immunoreactivity inepithelial structures including alveoli or bronchioli (x400).(C) Immunohistochemical staining of SP-A shows positive immunoreativity forepithelial structures including alveoli or bronchioli (x800).(D) Immunohistochemical staining of α-SMA is positive in spindle-shaped cells (x400).(E) Immunohistochemical staining of ER is positive in spindle-shaped cells (x400).(F) Immunohistochemical staining of PgR is positive in spindle-shaped cells (x400).