First Case of a Primary Lung Granulosa Cell Tumor With a Mutation in the Forkhead Box L2 Gene
Authors: Aya Izuwa, Gouji Toyokawa, Fumihiro Shoji, Koji Yamazaki, Seiya Momosaki, Kiyomi Furuya, Yuichi Yamada, Yoshinao Oda, Sadanori Takeo
Journal: Journal of Thoracic Oncology (2019)

A 68-year-old female was found to have pulmonary opacity in her right lower lung field on chest radiograph. She had a history of hysterectomy for uterine fibroids in her 30s with the bilateral preservation of her ovaries. Computed tomography showed a solid enhanced nodule 25 × 15 mm in the peripheral right lower lobe (Fig. 1A). The nodule showed heterogeneous high intensity on T2-weighted magnetic resonance imaging (MRI) (Fig. 1B) and inhomogeneous gradual signal increase on dynamic MRI (Fig. 1C) without any apparent diffusion coefficient decrease. Surgery was performed to partially resect the lower lobe. An intraoperative pathologic examination suggested the tumor to be a small cell carcinoma, so we performed right lower lobectomy (Fig. 2A).Figure 2Macroscopically, the tumor size was 21 × 14 × 11 mm (A). There was diffuse proliferation of homogeneous cells with well-defined borders and high cell densities in a low-power field (B). The chromatin was not dense, the long axis direction of the nucleus was not constant, and there was nuclear grooving (C). Immunostaining showed positivity for α-inhibin (D).View Large Image Figure ViewerDownload Hi-res image Download (PPT) The pathologic findings showed diffuse proliferation of homogeneous cells with well-defined borders and high cell densities in a low-power field (Fig. 2B). It showed an island structure, and small, uniform cells with a similar circular or egg-shaped circular nucleus observed. The chromatin was not dense, the long axis direction of the nucleus was not constant, and nuclear grooving was observed (Fig. 2C). Based on these findings, granulosa cell tumor (GCT) was suspected, and immunostaining was positive for α-inhibin, which is specific for GCT (Fig. 2D). Real-time polymerase chain reaction and direct sequencing identified a mutation in the Forkhead Box L2 (FOXL2) gene specifically found in adult GCT (Figs. 3A and 3B). Given the lack of any abnormal accumulation of fluorodeoxyglucose in the ovaries, our final diagnosis was primary pulmonary GCT. GCT is a sex cord interstitial tumor, and accounts for 2% to 5% of malignant ovarian tumors.1Crew K.D. Cohen M.H. Smith D.H. et al.Long natural history of recurrent granulosa cell tumor of the ovary 23 years after initial diagnosis: a case report and review of the literature.Gynecol Oncol. 2005; 96: 235-240Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar The pattern of progression is mainly locoregional in the pelvis, and distant metastasis is very rare.2Fox H. Agrawal K. Langley F.A. A clinicopathologic study of 92 cases of granulosa cell tumor of the ovary with special reference to the factors influencing prognosis.Cancer. 1975; 35: 231-241Crossref PubMed Scopus (260) Google Scholar A mutation in the FOXL2 gene, which is involved in follicular development and the production of estrogen and progesterone, and is a transcription factor necessary for the differentiation and proliferation of granulosa cells in the ovary, was identified as specific for GCT with a frequency of 100%.3Shah S.P. Köbel M. Senz J. et al.Mutation of FOXL2 in granulosa-cell tumors of the ovary.N Engl J Med. 2009; 360: 2719-2729Crossref PubMed Scopus (566) Google Scholar However, there are no reports regarding GCT originating from an organ other than the sex cord, thus making this the first report of primary lung GCT. Surgery is selected as the initial treatment for ovarian GCT in principle. Ovarian GCT has been reported to have a median recurrence-free survival of 5 years.4Lee Y.K. Park N.H. Kim J.W. et al.Characteristics of recurrence in adult-type granulosa cell tumor.Int J Gynecol Cancer. 2008; 18: 642-647Crossref PubMed Scopus (57) Google Scholar Regarding systemic chemotherapy, a platinum-based combination regimen is recommended.5Koukourakis G.V. Kouloulias V.E. Koukourakis M.J. et al.Granulosa cell tumor of the ovary: tumor review.Integr Cancer Ther. 2008; 7: 204-215Crossref PubMed Scopus (64) Google Scholar Although there are no reports regarding the optimal treatment for pulmonary GCT, such treatment should be performed in accordance with that for ovarian GCT. Two years after surgery, multiple solid nodules appeared on the right pleura, whereas no distant metastases were observed, and we performed right pleural tumor resection. Pathologically, the tumor was diagnosed of pleural seeding of GCT. The clinical features, such as rare distant metastasis and a tendency to progress locoregionally, were consistent with those of ovarian GCT. In conclusion, this is the first report of primary lung GCT. Even if the lesion is resected, locoregional recurrence such as the dissemination should be considered. We thank Brian Quinn for his critical comments on the manuscript.