Tumori, 97: 411-414, 2011
Endometrial metastasis of lung adenocarcinoma: a case report Marcello Tiseo1, Melissa Bersanelli1, Domenico Corradi2, Marco Bartolotti1, Francesco Gelsomino1, Rita Nizzoli1, Matteo Pesenti Barili3, and Andrea Ardizzoni1 1Medical
Oncology Unit, University Hospital of Parma, Parma; 2Department of Pathology and Laboratory Medicine, Section of Pathology, University Hospital of Parma, Parma; 3Radiology Unit, University Hospital of Parma, Parma, Italy
ABSTRACT
The female genital tract is an infrequent site of metastasis, in particular from extragenital primary tumors such as non-small cell lung cancer. Ovarian metastases have been described as disseminations of lung adenocarcinoma; rare cases of secondary localizations in adnexa, cervix and vagina were also observed in the literature, but none of these had endometrial involvement. We report the first case, to our knowledge, of non-small cell lung cancer with metastatic spread to the endometrium.
Introduction Although lung cancer is well known to metastasize frequently and widely, endometrial metastases as the dissemination site of this primary tumor have not yet been described in the literature. The most common gynecological manifestations of lung adenocarcinoma are ovarian metastases, which have been reported in several articles1-3. Microscopic involvement of the adnexa, with metastases in the uterine serosa and fallopian tube lumens, has also been described4. Two cases with vaginal localizations and a case of uterine cervical metastasis have also been reported5-7. Other lung cancer types have been observed to metastasize to the female genital tract, particularly small cell lung carcinoma (SCLC) and large cell carcinoma to the ovary1. Concerning endometrial involvement, only 1 case of SCLC and 1 case of welldifferentiated pulmonary neuroendocrine carcinoma metastasizing to this site have been reported in the literature8,9. Here we report a case of histologically confirmed primary lung adenocarcinoma with endometrial metastasis.
Case report A 58-year-old Caucasian woman, 40 packs/year smoker, came under our observation because of chest wall pain. Computed tomography (CT) showed a left pulmonary mass characterized by a solid portion with contiguous ground-glass areas, stellate borders, and pleural puckering (Figure 1); diffuse ground-glass pulmonary nodules, a right lung lesion, and a right eighth rib metastasis were also radiologically detectable. Fine-needle aspiration cytology of the largest pulmonary mass and surgical biopsy of the rib were both morphologically consistent with a diagnosis of nonsmall cell lung carcinoma (NSCLC), possibly adenocarcinoma. This was confirmed by immunohistochemical analysis, which was positive for cytokeratin 7 and thyroid transcription factor-1 (TTF-1), while being negative for cytokeratin 20, thyroglobulin, S100, HMB-45, and melan A (Figures 2A and 2B). Because of the advanced stage of the disease, the patient was treated with first-line chemotherapy within a placebo-controlled clinical trial administering 6 cycles of car-
Key words: non-small cell lung cancer, lung adenocarcinoma, endometrial metastasis. Correspondence to: Marcello Tiseo, Medical Oncology Unit, University Hospital of Parma, Via Gramsci 14, 43100 Parma, Italy. Tel +39-0521-702316; fax +39-0521-995448; e-mail
[email protected] Conflict of interest statement: No conflicts of interest for all authors. Received June 23, 2010; accepted October 21, 2010
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Discussion
Figure 1 - Imaging. CT scan shows the left lung lesion, characterized by a solid portion with contiguous ground-glass areas, stellate borders and pleural puckering.
boplatin, paclitaxel, and the antiangiogenic agent ASA404 or placebo, followed by maintenance therapy only with ASA404 or placebo. After this treatment, the clinical picture seemed stabilized. However, after 10 months the patient started complaining of vaginal bleeding and was submitted to a gynecological examination. Ultrasound imaging showed increased endometrial thickness (about 10 mm) and hysteroscopic biopsy confirmed the clinicoradiological suspicion of an endometrial metastasis from the primary lung cancer (Figure 2C). The tumor was a poorly differentiated and immunohistochemically positive for TTF-1 (Figure 2D), focally positive for cytokeratin 7, while negative for cytokeratin 20, myogenin, S100, and estrogen receptors. Estrogen receptors were also immunohistochemically negative in the lung and bone specimens, as tested at the time of the uterine biopsy. Whole-body CT scan revealed 2 new brain metastases as well as pulmonary disease progression. On this basis, second-line chemotherapy with pemetrexed was initiated. The metrorrhagia continued (although without any significant anemia), but considering the patient’s clinical impairment and the advanced stage of the disease, we decided against surgical resection of the uterus. The second-line chemotherapy was poorly tolerated with nausea, vomiting, and diarrhea; moreover, it did not give any clinical benefit. Because of drug toxicity and further disease progression (with new subcutaneous, hepatic, and adrenal metastases), chemotherapy was stopped and third-line treatment with erlotinib was initiated and is still being administered.
The endometrium is an unusual site for metastases from primary lung cancer. There are only rare cases in the literature of gynecological manifestations of lung cancer, particularly if we consider adenocarcinoma, the most frequent subtype of NSCLC1. Differently from our report describing endometrium involvement, the reported cases had metastases from NSCLC to the cervical canal and the uterine serosa. The latter was an incidental finding following hysterectomy and bilateral salpingo-oophorectomy for uterine carcinosarcoma. In fact, pathological examination revealed an uterine carcinosarcoma with other neoplastic foci in the fallopian tube lumens, the ovarian cortical tissue and the uterine serosa, consistent with metastatic lung carcinoma. The patient had undergone thoracic surgery for NSCLC 3 years prior to hysterectomy and she had suspicious mediastinal lymphadenopathy 16 months after the lung resection, suggesting slow disease progression with subsequent appearance of the uterine metastasis4. There have been only 2 reported cases of endometrial metastases from primary lung cancer, but neither of these patients had NSCLC8,9. One of them was a women affected by SCLC treated with chemoradiotherapy; during follow-up, ultrasound imaging showed a tumor mass on the anterior surface of the uterus. Hysterectomy evidenced a tumor lesion consistent with metastasis of primary SCLC (chromogranin, CD56 and synaptophysin positive); only the endometrial mucosa and myometrium were involved, without extension to the adnexa or cervical canal8. The clinical manifestation of gynecological metastases may mimic a primary gynecological tumor, with typical symptoms such as vaginal bleeding, as occurred in our patient. For a correct differential diagnosis it is necessary to consider the features that differentiate these lesions from primary gynecological carcinomas. When cancer lesions in the female genital tract exhibit unusual histological features, a metastasis should always be suspected. Immunohistochemistry is recommended when the pathological features do not support a gynecological origin, in order to link the lesions with a primary extragenital tumor with known immunohistochemical characteristics. In our case, similar immunohistochemical features were observed, proving the pulmonary origin of the endometrial lesion. A few primary endometrial adenocarcinomas are positive for TTF-1, which is commonly considered as sensitive and relatively specific for tumors of pulmonary/thyroid origin10. As regards the immunohistochemical expression of cytokeratins, endometrial adenocarcinomas are usually positive for cytokeratins 7 and 2011, while most pulmonary adenocarcinomas have a cytokeratin 7-positive and cytokeratin 20-negative immunophenotype10, like in our case. In
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A
B
C
D
Figure 2 - Histopathology. A) Low-power histological appearance of the rib metastasis. The poorly differentiated neoplastic cells diffusely infiltrate the intertrabecular spaces; there is some reactive new bone formation throughout (arrow). B) TTF-1 nuclear positivity of the tumor cells in the bone metastasis (arrow). C) Low-power histological view of the hysteroscopic biopsy with large clusters of poorly differentiated epithelial elements; arrows indicate 2 small fragments of normal endometrial glands. D) TTF-1 nuclear positivity of the same tumor cells shown in C; the arrow indicates TTF-1-negative endometrial glands. Original magnifications: A and C: ×10, B and D: ×20. A and C: hematoxylin and eosin staining.
addition to being positive in the great majority of endometrial carcinomas, estrogen receptors (negative in our specimens) are expressed by a very small fraction of pulmonary adenocarcinomas12. The natural history of the disease should be taken into account when interpreting the new findings in the context of the primary tumor. In our patient disease progression, with neurological symptoms and worsening clinical conditions due to the appearance of metastases also in extragenital sites, was clearly demonstrated 2 years after the discovery of the pulmonary masses. This clinical trend was largely in keeping with a lung carcinoma with metachronous metastases and excluded the possibility of occult primary endometrial neoplasia. In conclusion, we have reported the first case of lung adenocarcinoma metastasizing to the endometrium, demonstrating the ubiquity of hematogenous dissemi-
nation from NSCLC and suggesting to consider the possibility of a pulmonary origin in case of gynecological lesions with uncertain pathological features.
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