Huge ovarian masses in a lung adenocarcinoma patient, mimicking a primary ovarian cancer
Chia-Hung Hsu1, Nien-Yi Chang2, Gee-Chen Chang1,3,4*
Authorship Note:
1Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
2Department of Pathology, Taichung Veterans General Hospital, Taichung, Taiwan
3Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
4Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
* To whom correspondence should be addressed: Gee-Chen Chang
Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
No.1650, Sec. 4, Taiwan Boulevard, Taichung 40705, Taiwan.
E-mail:
Tel.: +886423592525 ext. 3250Fax: +886423741320
Running Title: Huge ovarian masses in a lung adenocarcinoma patient
Abstract
Most lung cancer patients present with metastatic disease. It is very important to diagnose the primary or synchronous malignancy in multiple organ metastasis patients. Herein, we present a female lung adenocarcinoma patient with discrepant treatment response between huge bilateral ovarian masses and primary lung cancer. She received bilateral oophorectomy with omentectomy for further differential diagnosis and severe compression symptoms. Pathology and immunohistochemical study findings were consistent with lung origin. Due tohuman epidermal growth factor receptor 2(HER-2)mutation with exon 20 insertion, we combined afatinib with a chemotherapy regimen as the treatment strategy. She is regularly followed up at our outpatient department.HER-2 mutation with exon 20 insertion is a potential novel treatment target and afatinib is an option of targeted therapy. Lung cancer with uncommon metastatic sites implicated a poor prognosis. Additional local treatment for uncommon oligometastases should be considered in highly selected patients.
Key words: Lung cancer, adenocarcinoma, ovarian metastasis, HER-2 mutation.
Introduction
Lung cancer is the leading cause of cancer death both in men and women, and about 60% of lung cancer patients were metastasis at diagnosis [1]. The most common metastatic sites in non-small cell lung cancer (NSCLC) were brain, bone, liver and adrenal glands[2]. In the other organs metastases were rare. It is very important to diagnose the primary or synchronous malignancy in multiple organ metastasis patients via clinical, radiological and pathological assessments because of the different treatment strategies required for different diseases.
Approximately 10% of ovarian tumors are metastatic from other organs. In previous studies, most ovarian metastasis originated from stomach, breast and colon cancer. Lung cancer is a rare primary origin malignancy of them [3-5]. Herein, we present a female lung adenocarcinoma patient with discrepant treatment response between huge bilateral ovarian masses and primary lung cancer, mimicking a primary ovarian cancer.
Case Report
This 43 year-old woman denied systemic disease, and presented to our outpatient department in 2014/11 having suffered with chronic cough with some blood-tinged sputum for 6 months, and progressive abdominal fullness in the most recent month. She is a kindergarten teacher, and has never smoked, and there is no family history of lung cancer. About one year ago, a small lung lesion was incidentally found on a chest X-ray during a health examination. However, she refused further diagnostic evaluations and did not follow up regularly. She presented to the outpatient department again with chronic cough with some blood-tinged sputum, and abdominal fullness. Physical examination showed a soft and distended abdomen with a palpable mass in the lower part, along with bilateral mild crackling breathing sound over the lower lung field. A chest X-ray revealed an irregular lung mass about 2x2.5 cm with bilateral pleural effusion, in the left lower lung field. Computed tomography showed anirregular-shapedinhomogeneous solid lung mass (32 x 30mm) in the left lower lobe, mild pleural traction and some adjacent nodules in the left upper lobe and left lower lobe, measuring about 5x5mm, and two lobulated masses with mixed cystic and solid components noted at the bilateral adnexa, measuring about 13.7x6.4cm at right side and 8.6×5.8cm at left side, accompanied by moderate ascites, peritoneal thickening and multiple osteolytic lesions in the thoracic and lumbar spines. Duodenoscopy and colonoscopy were unremarkable. Histological study of the bronchoscopic biopsy specimen showed adenocarcinoma, moderately to poorly-differentiated. Immunohistochemical study revealed positive staining for cytokeratin (CK) 7, negative staining for CK20, and positive nuclear staining for thyroid transcription factor-1 (TTF-1).Based on the clinical history, image and pathology report, lung adenocarcinoma with diffuse metastasis was first considered. Due to wild-type epidermal growth factor receptor (EGFR) but mutant HER-2 with exon 20 insertion, she received cisplatin 75 mg/m2 plus pemetrexed 500 mg/m2 every three weeks and afatinib 30 mg/day, a highly selective blocker of the ErbB family, including EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4).
After treatment for six cycles of cisplatin plus pemetrexed, the primary lung mass, metastatic lung nodules, pleural effusion, ascites regressed but bilateral adnexa had progressed compared to initial presentation, measuring right side 15.6 x 9.4cm, left side 9.8 x 6.9cm and resulting in bilateral mild hydronephrosis (Figure 1). She also complained of progressive abdominal fullness, flank soreness and urinary frequency. She received bilateral oophorectomy with omentectomy for further differential diagnosis and severe compression symptoms. Gross appearance of the cross-section of the ovarian tumor showed multiple loculated cystic components with yellowish fluid and huge solid part (Figure 2). Pathology disclosed moderate to poorly-differentiated adenocarcinoma. Immunohistochemical study revealed positive nuclear staining for TTF-1 and negative finding of PAX-8 and GATA-3 (Figure 3). HER-2 mutation with exon 20 insertion was noted in both ovarian specimens.According to the pathology, immunohistochemical and geneticstudy, metastatic adenocarcinoma from the lung is first considered. Due to divergent treatment response of lung cancer, we shifted chemotherapy regimen to paclitaxel 60mg/m2 and afatinib after operation wound healing and observation of an acceptable general condition. Now, she is still followed up at our outpatient department.
Discussion
The common metastasis sites of lung cancerare brain (47%), followed by bone (36%), liver (22%), adrenal glands (15%), body wall (13%), lung (11%), distant lymph node (10%), spleen (6%), spinal canal (3%), and pancreas (1%) [6]. Ovarian metastasis is rare among lung cancers but not unusual in other cancers. The study by de Waal et al. reviews 116 patients diagnosed with ovarian metastasis between 1985 and 2007. The gastrointestinal tract malignancy was the most common primary origin (39%, including 20% from large intestine, 6% from stomach, 2% from small intestine), followed by breast cancer (28%) and endometrial cancer (20%) Not a single one was from lung cancer [7]. In another report, only one in 97 cases of ovarian metastasis was from lung cancer [5].Irving and Young reported 32 lung carcinoma patients with metastasis to the ovary. In regard to the histology type of lung carcinoma, 44% of the cases were small cell carcinoma, 34% adenocarcinoma, and 16% large cell carcinoma. A previous history of lung cancer was recorded in 53% of the cases when ovarian metastasis was diagnosed, 31% were synchronous and 16% were diagnosed of lung cancer after ovarian metastasis. Bilateral ovarian involvement was presented in 34% of all the cases, right side in 41% and left side in 25%.
Immunohistochemical stain is a helpful tool for differential diagnosis of malignancy origin. CK7-/CK20+ is seen in more than 90% of colon adenocarcinoma, while more than 80% of lung, breast and ovarian adenocarcinoma are CK7+/CK20-. TTF-1 expression is found in lung and thyroid tumors with sensitivity ranged from 62% to 89% and specificity, 98% to 100%. It also reported in non-pulmonary malignancy, such as breast and colon adenocarcinoma [8-11]. Combining different immunohistochemical stain results helps identifying the origin and establishes appropriate treatment strategy.
Although the uncommon, metastatic sites were classified as M1b, stage IV according to the American Joint Committee on Cancer (AJCC) 7th edition[12]. Is there clinical difference between the metastatic sites? A study by Niu et al. reviewed 2,872 NSCLC patients with distant metastases at the Guangdong Lung Cancer Institute from 2006 to 2012. The uncommon metastasis included metastatic sites other than the brain, bone, liver, adrenal glands, thoracic cavity and distant lymph nodes. Overall, 193 patients were classified as uncommon metastasis among 2872 NSCLC patients, accounting for 6.7% of total patients. The frequency of uncommon metastatic site is soft tissue (2.86%), followed by kidney (0.87%), peritoneum (0.84%), spleen (0.66%), pancreas (0.59%), intestine (0.24%) and ovary (0.07%). The median overall survival of uncommon metastasis site patients was significantly shorter than that of common metastasis site patients (13.0 months versus 18.3 months, P<0.01). It implied that cancer cells in uncommon metastasis sites behave more aggressive and invasive. Additional local treatment for uncommon oligometastases should be considered in highly selected patients [13, 14].
With respect to HER-2 mutation with exon 20 insertion, it accounts for about 2% in all lung adenocarcinoma in our previous study [15]. There is some evidence suggesting afatinib as a potential novel treatment option. Schallier et al. reported five patients who were identified with HER2 mutation and have previously failed multiple chemotherapy regimens and the EGFR and/or HER2 inhibitors, including erlotinib, trastuzumab and lapatinib. Afatinib showed clinical benefit in disease-related symptoms relief and radiological partial response or stable disease. The time to progression on afatinib treatment is about 3~4 months [16]. Therefore, we prescribed afatinib and adjusted the dose to 30mg daily due to the patient’s small body size.
In conclusion, differentiating primary or secondary ovarian tumor is the most important issue in patientswith diffuse metastasis. The uncommon metastasis site is a diagnostic challenge for clinicians. Multidisciplinary approaches, including clinical history, radiological, pathological, immunohistochemical, and genetic study, are crucial. Local treatment could be considered in highly selected patients as uncommon metastasis implicating a poor prognosis.
Reference
1.Siegel RL, Miller KD and Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016; 66(1):7-30.
2.Quint LE, Tummala S, Brisson LJ, et al. Distribution of distant metastases from newly diagnosed non-small cell lung cancer. Ann Thorac Surg. 1996; 62(1):246-250.
3.Holtz F and Hart WR. Krukenberg tumors of the ovary: a clinicopathologic analysis of 27 cases. Cancer. 1982; 50(11):2438-2447.
4.Ulbright TM, Roth LM and Stehman FB. Secondary ovarian neoplasia. A clinicopathologic study of 35 cases. Cancer. 1984; 53(5):1164-1174.
5.Kondi-Pafiti A, Kairi-Vasilatou E, Iavazzo C, et al. Metastatic neoplasms of the ovaries: a clinicopathological study of 97 cases. Arch Gynecol Obstet. 2011; 284(5):1283-1288.
6.Niu FY, Zhou Q, Yang JJ, et al. Distribution and prognosis of uncommon metastases from non-small cell lung cancer. BMC Cancer. 2016; 16(1):149.
7.de Waal YR, Thomas CM, Oei AL, et al. Secondary ovarian malignancies: frequency, origin, and characteristics. Int J Gynecol Cancer. 2009; 19(7):1160-1165.
8.Hecht JL, Pinkus JL, Weinstein LJ, et al. The value of thyroid transcription factor-1 in cytologic preparations as a marker for metastatic adenocarcinoma of lung origin. Am J Clin Pathol. 2001; 116(4):483-488.
9.Reis-Filho JS, Carrilho C, Valenti C, et al. Is TTF1 a good immunohistochemical marker to distinguish primary from metastatic lung adenocarcinomas? Pathol Res Pract. 2000; 196(12):835-840.
10.Xu B, Thong N, Tan D, et al. Expression of thyroid transcription factor-1 in colorectal carcinoma. Appl Immunohistochem Mol Morphol. 2010; 18(3):244-249.
11.Comperat E, Zhang F, Perrotin C, et al. Variable sensitivity and specificity of TTF-1 antibodies in lung metastatic adenocarcinoma of colorectal origin. Mod Pathol. 2005; 18(10):1371-1376.
12.Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2007; 2(8):706-714.
13.Weickhardt AJ, Scheier B, Burke JM, et al. Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer. J Thorac Oncol. 2012; 7(12):1807-1814.
14.Griffioen GH, Toguri D, Dahele M, et al. Radical treatment of synchronous oligometastatic non-small cell lung carcinoma (NSCLC): patient outcomes and prognostic factors. Lung Cancer. 2013; 82(1):95-102.
15.Hsu KH, Ho CC, Hsia TC, et al. Identification of five driver gene mutations in patients with treatment-naive lung adenocarcinoma in Taiwan. PLoS One. 2015; 10(3):e0120852.
16.De Greve J, Teugels E, Geers C, et al. Clinical activity of afatinib (BIBW 2992) in patients with lung adenocarcinoma with mutations in the kinase domain of HER2/neu. Lung Cancer. 2012; 76(1):123-127.
Figure 1.(A)(B) Initial presentation. Lung nodule with huge ovarian tumors. (C)(D) After six cycles of cisplatin and pemetrexed, discrepant treatment response between primary lung cancer, pleural effusion and huge ovarian tumors.
Figure 2. Gross appearance of the cross-section of the ovarian tumor. It is composed of multiple loculated cystic components, with yellowish fluid and a huge solid part.
Figure 3. (A) The tumor cells of the ovarian mass are arranged in solid nested pattern (H&E, 40×). (B) The tumor cells are large nuclei with prominent nucleoli, abundant cytoplasm and in glandular structure, compatible with adenocarcinoma (H&E, 400×). (C) The tumor cells express positive finding of TTF-1 in immunohistochemical study, which are compatible with lung origin (TTF-1, 400×). (D) The tumor cells did not express PAX-8 (PAX-8, 400×).
中文標題：龐大的卵巢腫瘤在肺腺癌病人，貌似原發性卵巢癌
中文著者姓名：許嘉宏１，張念伊２，張基晟１３４
1台中榮民總醫院內科部胸腔內科
2台中榮民總醫院病理部
3國立陽明大學醫學系
4國立中興大學生物醫學研究所
中文摘要：大多數的肺癌病人就醫時，已經有遠處轉移。在多處器官轉移的病人，診斷原發癌症和是否同時存在其他癌症是臨床很重要的議題。在此篇文章，我們報告一位女性肺腺癌病人，原發肺癌和雙側卵巢腫癌治療成效有明顯差異。為了進一步鑑別診斷卵巢腫瘤和改善明顯的壓迫症狀，她接受雙側卵巢切除和網膜切除術，病理和免疫組織化學染色結果和肺癌表現相符合。因為具有HER-2突變（exon 20 insertion）我們合併化療藥物和afatinib做為治療，現在病人仍規則於門診追蹤。HER-2突變（exon 20 insertion）可能是一個新的標靶治療標的，而afatinib是可選用的口服標靶藥物。肺癌合併少見的轉移位置暗示著病人有較差的預後，針對少見的轉移腫瘤，部份病人需仔細考慮額外的局部治療。
關鍵字：肺癌，腺癌，卵巢轉移，HER-2 突變
通訊作者：張基晟
研究單位：台中榮民總醫院內科部胸腔內科
地址：台中市西屯區臺灣大道四段1650號
1