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Soonchunhyang Med Sci > Volume 21(2); 2015 > Article
Choi, Park, Kim, Yoon, Ro, and Nam: Uterine Cervix Metastasis in Lung Adenocarcinoma with Anaplastic Lymphoma Kinase Rearrangement


The importance of anaplastic lymphoma kinase (ALK) as an oncogene in non-small cell lung cancer (NSCLC) has emerged as a major concern due to a dramatic clinical effect of targeted therapy. As compared with the research for targeted therapy, the study about clinicopathological characteristics for ALK positive NSCLC hasn’t been worked enough. Here, we describe a 35-year-old woman diagnosed with stage IVb NSCLC with ALK rearrangement. During evaluating her disease, a metastatic lesion to uterine cervix was found. Although lung cancer metastasis to female genital tract is rare, we also present case series that show a metastasis to the female genital tract in NSCLC with ALK rearrangement. These case series could suggest that ALK positive NSCLC has distinct metastatic pattern.


Metastatic lung cancer to the female genital tract is too rare. There are a few reported cases of metastasis to the female genital tract-endometrium, cervix, vagina, and ovary. Clinicians have trouble to differentiate metastatic carcinoma from gynecological origin tumor. We report a case of lung adenocarcinoma with metastasis to the uterine cervix. This is the first case of uterine cervix metastasis of anaplastic lymphoma kinase (ALK) rearranged lung adenocarcinoma. Recently, three cases of ovarian metastasis from ALK rearranged non-small cell lung cancer (NSCLC) have been reported [13]. These reports could suggest ALK rearranged lung cancer would have distinct mechanism of metastasis.


A 35-year-old woman, non-smoker, was referred to the emergency department complaining dyspnea. In the previous hospital, seven days before, computed tomography (CT) on chest showed circumscribed mass with internal cavity and pericardial effusion. She had taken antibiotics, but she persisted dyspnea. The next day, she exacerbated of dyspnea. Chest x-ray showed bilateral pleural effusion and a subsequent CT demonstrated increased amount of pericardial effusion and pleural effusion and cavitary mass lesion in right lower lobe (RLL). Echocardiogram showed tamponade physiology, immediately pericardiocentesis was done and pleural fluid was also drained. To evaluate the cause of effusion, autoimmune study and tumor marker was done. Cancer antigen-125 (CA-125) was elevated as 1,000 U/mL. Being suspicious of ovarian cancer, we checked gynecological examination and pap smear. Transvaginal ultrasonography just showed a 0.7-cm-sized uterine myoma and CT scan on pelvic didn’t show any suspicious lesion in both ovary and uterus. After that, CT-guided percutaneous biopsy of the cavitary lung mass confirmed lung adenocarcinoma, and pleural fluid cell block showed also adenocarcinoma. Immunohistochemical stain and fluorescence in situ hybridization (FISH) analysis were positive for ALK translocation, but negative for epidermal growth factor receptor. There was no evidence of metastasis to brain and bone, but positron emission tomography (PET)-CT showed hypermetabolic malignant tumor in RLL with metastatic lymph nodes in both posterior cervical space, supraclavicular area, and peribronchial area. A pap smear also showed adenocarcinoma (Fig. 1A). To differentiate origin of cervical adenocarcinoma, biopsy for cervix guided by colposcopy was done. Pathologic result was chronic cervicitis. Because lung metastasis to the cervix was rare, immunohistochemistry was performed on cervix smear using thyroid transcription factor-1 (TTF-1). The cervical smear was strong positive for TTF-1 (Fig. 1B). She was finally diagnosed cervical metastasis from lung adenocarcinoma with ALK rearrangement. She was initially treated with crizotinib with partial response after 2 month. After 5 month, follow-up CT scan on chest showed progressed disease in lung cancer. Now she has treated for pemetrexed, cisplatin, and crizotinib.


Lung cancer metastasis to the female genital tract is too rare. Only some cases have been reported including involvement of ovary, endometrium, vagina, and cervix. We identified eleven patients with metastatic activity to the female genital tract (Table 1) [414]. Because of a lack of clinical information, we excluded earlier reported 32 cases of ovarian metastasis by Irving and Young [15]. Six patients of them were metastasis to ovarian, two of them to cervix, two patients to vagina, and one patient were to endometrium. Seven patients had metastatic disease at diagnosis. Six patients of them had complained of vaginal bleeding and other three patients had complained of urinary frequency or abdominal pain. The others were detected the suspicious lesion for screening test—pap smear or CT scan. All metastatic lesions were confirmed by biopsy. Especially, nine patients were adenocarcinoma with positive for TTF-1. In our case, a patient didn’t complain for gynecologic symptom, so elevated CA-125 level was a clue to be suspicious of gynecologic malignancy. A pap smear showed adenocarcinoma, and positive for TTF-1.
ALK rearrangements define a distinct molecular subtype of lung cancer. ALK positive NSCLC tends to be present with no smoking habit, younger age, and adenocarcinoma. Fan et al. [16] reported ALK rearrangements tended to be present in NSCLC patients with tumor stage IV. Doebele et al. [17] reported that ALK gene rearrangement was significantly associated with pericardial disease. Recently three cases which are lung adenocarcinoma with ALK rearranged showing ovarian metastasis were reported [13] (Table 2). A patient of case 1 was suspected metastasis as PET-CT showed high uptake in ovaries at first diagnosed time, and patients of case 2 and 3 were suspected recurrence after chemotherapy. All three patients have been done oophorectomy to differentiate double primary cancer, biopsy confirmed metastatic lung adenocarcinoma. Less common sites of metastatic spread were also reported in ALK positive patients including gastric cardia or orbital area [18,19]. These cases suggest ALK rearranged lung carcinoma has a distinct metastatic behavior.
Testing for ALK translocation-FISH in lung cancer was commercialized for only 5 years ago, so study for ALK negative versus ALK positive lung adenocarcinoma wasn’t reported enough. We suppose that many patients of lung cancer metastasis to the genital tract wouldn’t been caught. In the reported cases, clinicians initially suspected a primary gynecological tumor, and examined the gynecologic study.
In conclusion, we report an ALK gene rearranged metastatic lung adenocarcinoma to uterine cervix. Recent reports which are ALK positive lung adenocarcinoma with less site of metastatic spread suggest ALK positive lung adenocarcinoma has different metastatic mechanism. Surely, further study for metastatic mechanism of ALK positive lung cancer and additional case report is necessary. To detect metastatic lesion, we recommend a pap smear and a biopsy of any suspicious lesion.

Fig. 1
(A) Pap smear liquid-based cytology finding showed adenocarcinoma and epithelial cell abnormalities (papanicolaou stain, ×200). (B) The adenocarcinoma compounds react positively for thyroid transcription factor-1 (immunohistochemical staining of thyroid transcription factor-1, ×200).
Table 1
Patients with metastatic lung cancer to the female genital tract
Case no. Author (year) Age (yr) Sex Metastatic site Smoking history Nationality Time to diagnose the metastatic lesion Clinical manifestation Histologic finding Method of confirmative biopsy Treatment
1 Yeh et al. [4] (2003) 63 F Both ovaries Never Chineses Recurrent, 3 year Vaginal bleeding, urinary symptom Bronchioloalveolar carcinoma Surgery Surgery
2 Jahnke et al. [5] (2005) 67 F Vagina, bladder Unknown Unknown Recurrent, 2 year Urinary symptom Adenocarcinoma Surgery Surgery
3 Parini et al. [6] (2007) 73 F Adexa, uterine serosa, fallopian tube, ovary 40 PYR Unknown Recurrent, 3 year Vaginal bleeding Adenocarcinoma Surgery Surgery
4 Peedell and Dykes [7] (2007) 53 F Vagina 20 PYR Unknown At presentation Vaginal bleeding Squamous carcinoma Ultrasound-guided biopsy CTx, RT
5 Khana et al. [8] (2007) 48 F Uterine cervix Unknown African American At presentation None Adenocarcinoma PAP smear, cervical biopsy Erlotinib
6 Kai et al. [9] (2009) 69 F Uterine cervix Unknown Japanese Recurrent, 4 year Vaginal bleeding Adenocarcinoma PAP smear, cervical biopsy CTx
7 Botana et al. [10] (2009) 54 F Right ovary Never Unknown At presentation Vaginal bleeding Adenocarcinoma Surgery Unknown
8 Tiseo et al. [11] (2011) 58 F Endometrium 40 PYR Caucasian At presentation Vaginal bleeding Adenocarcinoma Endometrial biopsy CTx, Erlotinib
9 Ketata et al. [12] (2011) 28 F Right ovary Never Unknown At presentation Urinary symptom Adenocarcinoma Surgery Surgery
10 Cengiz et al. [13] (2013) 49 F Left ovary Unknown Unknown At presentation Abdominal pain Adenocarcinoma Surgery Surgery, CTx
1114 Losito et al. [14] (2013) 37 F Right ovary Never Unknown At presentation None Adenocarcinoma Surgery CTx, RT, Bevacizuma

F, female; PYR, pack-year; CTx, chemotherapy; RT, radiotherapy; PAP, papanicolaou.

Table 2
Patients with female genital tract metastasis in non-small cell lung adenocarcinoma with ALK rearrangement
Case no. Author (year) Age (yr) Sex Metastatic site Nationality Stage at first diagnosed lung cancer 1st line therapy at first diagnosed lung cancer Time to diagnose the metastatic site Sign Histologic finding ALK translocation by FISH Method of confirmative biopsy to metastatic lesion Treatment after diagnosed metastatic lesion
1 Fujiwara et al. [1] (2013) 39 F Both ovaries Japan Stage IIIA Right middle lobectomy, adjuvant CTx 20 mo Abnormal PET-CT finding Adenocarcionma + Left salpingo-oophorectomy, right ovarian cystectomy Surgery, RT, crizotinib
2 Lee et al. [2] (2014) 54 F Both ovaries Korean Stage IVB 1st CTx, 2nd CTx, palliative RT At presentation Abnormal PET-CT finding Adenocarcinoma + Laparoscopic bilateral salpingo-oophorectomy Surgery, 3rd line CTx
3 West et al. [3] (2014) 50 F Both ovaries Unknown Stage IVB CTx 38 mo Abnormal PET-CT finding Adenocarcinoma + Abdominal hysterectomy c bilateral salpingo-oophorectomy Surgery, Crizotinib

ALK, anaplastic lymphoma kinase; FISH, fluorescence in situ hybridization; F, female; CTx, chemotherapy; PET-CT, positron emission tomography-computed tomography; RT, radiotherapy.


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