|Year : 2019 | Volume
| Issue : 2 | Page : 103-106
Pulmonary pleomorphic carcinoma harboring epidermal growth factor receptor mutation: Response to afatinib
Abeer Hussien Anter1, Majid Al-Jahel2, Rasha Mohamed AbdelLatif3, Mohamed Fouad AbdELmohsen4, Ahmed Shata5
1 Department of Clinical Oncology and Nuclear Medicine, Faculty of Medicine, Mansoura University, Egypt; Department of Oncology, King Fahad Hospital, Madinah, Saudi Arabia
2 Department of Oncology, King Fahad Hospital, Madinah, Saudi Arabia
3 Department of Clinical Oncology and Nuclear Medicine, Faculty of Medicine, Mansoura University, Egypt
4 Department of Oncology, King Fahad Hospital, Madinah, Saudi Arabia; Department of Clinical Oncology and Nuclear Medicine, Faculty of Medicine, Suez Canal University, Egypt
5 Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Egypt
|Date of Submission||14-Jul-2018|
|Date of Decision||16-Oct-2018|
|Date of Acceptance||18-Oct-2018|
|Date of Web Publication||31-May-2019|
Dr. Abeer Hussien Anter
Department of Clinical Oncology and Nuclear Medicine, Faculty of Medicine, Mansoura University, Mansoura
Source of Support: None, Conflict of Interest: None
Pulmonary pleomorphic carcinoma (PPC) of the lung is a rare type of non-small cell lung cancer, exhibiting aggressive behavior and resistance to chemotherapy. We report a case of a 56-year-old female, diagnosed with PPC of the lung at clinical Stage IV in July 2017. She underwent first-line chemotherapy. The disease progressed after 6 cycles of chemotherapy, and we shift to afatinib due to presence of epidermal growth factor receptor (EGFR) mutation in exon 19. We then started second-line treatment in the form of molecular targeted therapy (afatinib), to which she had a partial response. Hence, we recommend the evaluation of driver gene alterations such as EGFR in the treatment of advanced PPC.
Keywords: Afatinib, chemotherapy, epidermal growth factor receptor, pulmonary pleomorphic carcinoma
|How to cite this article:|
Anter AH, Al-Jahel M, AbdelLatif RM, AbdELmohsen MF, Shata A. Pulmonary pleomorphic carcinoma harboring epidermal growth factor receptor mutation: Response to afatinib. J Cancer Res Pract 2019;6:103-6
|How to cite this URL:|
Anter AH, Al-Jahel M, AbdelLatif RM, AbdELmohsen MF, Shata A. Pulmonary pleomorphic carcinoma harboring epidermal growth factor receptor mutation: Response to afatinib. J Cancer Res Pract [serial online] 2019 [cited 2019 Jun 17];6:103-6. Available from: http://www.ejcrp.org/text.asp?2019/6/2/103/259487
| Introduction|| |
Pulmonary pleomorphic carcinoma (PPC) is rare with an incidence ranging from 0.1% to 0.4% of all lung cancers., Pleomorphic carcinoma (PC) is defined as poorly differentiated adenocarcinoma, squamous cell carcinoma, or large cell carcinoma containing sarcomatoid components of spindle cells and/or giant cells in at least 10% of the cells or a carcinoma comprised entirely of giant and spindle cells.,
PC has a more aggressive clinical course and worse prognosis than other histological types of non-small cell lung cancer (NSCLC). Furthermore, some recent reports have noted that PPC is often refractory to the chemotherapy usually used for NSCLC. Due to its rarity, no optimal treatment for PPC has yet been established.,,
Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are effective in prolonging the progression-free survival of patients with NSCLC, typically adenocarcinoma, bearing active EGFR mutations in their tumors. However, information on the EGFR mutation status of PPC is sparse.
Herein, we report a rare case of metastatic PPC with an EGFR exon 19 deletion. We present the clinical course and the efficacy of molecular targeted therapy (afatinib) in this case.
| Case Report|| |
A 56-year-old woman who had never smoked visited our department because of a persistent nonproductive cough, shortness of breath, and right chest pain that had begun one month before her visit. She denied any history of smoking or lung disease. She was being treated for diabetes mellitus, hypertension, and hypothyroidism with oral medications.
A physical examination revealed that she was overweight, alert, conscious, oriented, and afebrile. She was hemodynamically stable at the time of the examination. Her blood pressure was 132/76 mmHg and oxygen saturation was 96% on 3L oxygen. The only finding of note during her respiratory examination was decreased air entry on her right side. No abnormal findings were noted on cardiac, abdominal, or skin examinations.
Her basic laboratory tests including a complete blood count, kidney function, and liver function tests were all normal.
A computed tomography (CT) scan of her chest, abdomen and pelvis was performed, which showed a huge heterogeneous soft tissue mass in the right lobe measuring 14.5×7.5 cm and associated with pleural deposits, enlarged mediastinal lymph nodes and mild pleural effusion and a single metastatic focal hypodense lesion in the liver measuring 17x17 mm [Figure 1].
|Figure 1: (a) Computed tomography scan showed a huge tumor in the Rt lung. (b) Abdominal CT showed a single metastatic focal hypodense lesion in the liver measuring 17x17 mm|
Click here to view
A bone scan was negative for metastasis. She then underwent a CT-guided biopsy that failed; so, she underwent thoracotomy with a wedge biopsy from the lung mass and pleural nodules.
Light microscopic findings revealed that the tumors consisted mainly of malignant epithelial cells (likely squamous cell carcinoma) accounting for 80% and spindle/giant cells (pleomorphic component) accounting for about 20%. Thus, the disease had two histological elements, resulting in the diagnosis of PPC [Figure 2]a and [Figure 2]b.
|Figure 2: (a and b) Hematoxylin and eosin staining demonstrated pleomorphic carcinomas with giant and spindle cells|
Click here to view
The tumor cells were positive for P63, CK5/6, and CK7, and there was weak nuclear positivity for thyroid transcription factor (TTF-1). The final histopathological diagnosis was PC of the lung (the poorly differentiated squamous cell carcinoma component accounted for 80% of the tumor and the pleomorphic component accounted for about 20%). Rt pleural nodules showed PC deposits [Figure 3]a and [Figure 3]b.
|Figure 3: (a) Immunohistochemistry analysis was positive for P63. (b) Immunohistochemistry analysis was positive for Ck7|
Click here to view
Paraffin-embedded tumor specimens were sent for EGFR analysis.
Treatment and follow-up
On July 2017, she started chemotherapy consisting of carboplatin and gemcitabine. She had a stable disease course after 3 cycles; however, the disease progressed after finishing 6 cycles of chemotherapy. The chest and abdomen CT revealed an increase in the size of the lung mass and increase in the number and size of liver lesions with the new appearance of bone metastasis indicating disease progression. An EGFR test revealed a deletion mutation in exon 19; so, we started afatinib (40 mg PO per day). In addition, she was started on bisphosphonates for bone metastasis. She tolerated the treatment very well with only grade 1 diarrhea and grade 1 skin rash, which were controlled with medications. Six weeks after initiation of afatinib, her treatment was reassessed by new imaging that showed a partial response in both lung and liver lesions [Figure 4]a and [Figure 4]b. She was doing well after 7 months of afatinib treatment without evidence of tumor progression. Currently, she receives treatment from the oncology clinic as an outpatient.
|Figure 4: Chest computed tomography images before (a) and 6 weeks after afatinib treatment (b)|
Click here to view
| Discussion|| |
PC is one of the five subtypes of sarcomatoid carcinoma of the lung which also include spindle cell carcinoma, giant cell carcinoma (a tumor almost entirely composed of giant cells), carcinosarcoma (a mixture of NSCLC and sarcoma containing heterologous elements), and biphasic pulmonary blastoma (a tumor composed of embryonal-type epithelial elements and primitive mesenchymal stroma).
While light microscopy is sufficient to diagnose most of these tumors, immunohistochemistry can be useful in certain settings. Immunohistochemistry can be used to help determine the histological type of non-small lung carcinoma. In general, CK5/6 and p63 are markers of squamous cell carcinoma whereas SP-A and TTF-1 are markers of adenocarcinoma. Staining with CK7 and CK20 antibodies can help discriminate between primary lung carcinoma and metastatic lung carcinoma. In addition, pan cytokeratin (CAM 5.2 and LP 34) has been reported to be present in sarcomatoid carcinoma of the lung.
There is no specific clinical presentation although patients may present with cough, dyspnea, hemoptysis, chest pain, or weight loss.
PPC has a more aggressive clinical course and a worse outcome than other NSCLC. However, there is currently no consensus on the treatment of PC. Surgery is usually the first choice for the early stage of PC. Palliative chemotherapy is always used in advanced PPC. Previous retrospective studies and case reports have suggested that PPC is often refractory to the chemotherapy regimens used for the active treatment of NSCLC.,,,
In NSCLC, the discovery that somatic alterations of driver genes, including EGFR and anaplastic large kinase genes, are found in a subset of lung adenocarcinomas and are associated with sensitivity to molecular target therapy has provided a rationale for the development of therapies for NSCLC.,,, Some reports have noted that EGFR mutations occur in 15%–20% of patients with PPC but that the response to EGFR TKIs receptor was weak and transient because of tumor heterogeneity.,,,,
In our case, we did not wait for the result of EGFR analysis because of a deterioration in the clinical situation of the patient and the need for rapid intervention; so, she commenced first-line chemotherapy with carboplatin and gemcitabine. She experienced disease progression after six cycles of treatment before the result of EGFR analysis revealed an exon 19 deletion mutation. She then started afatinib with subjective improvement. Imaging confirmed her improvement as it showed an excellent partial response in both primary lung tumors and liver lesions. In contrast, Saitoh et al. reported a case report of lung PC with an exon 19 EGFR deletion mutation that showed a poor response to gefitinib and the patient died of progressive disease 4 months after the initiation of gefitinib therapy. This may be explained by the difference in pathology of the tumors. In Ushiki's case, the sarcomatous cells constituted more than 95% of the malignant tissues and the remaining cells were adenocarcinoma while in our case, the sarcomatous part only constituted 20% of the malignant cells. The FDA has approved the indication of afatinib in the second-line treatment of advanced squamous cell carcinoma, and the basic cellular component was squamous cell carcinoma in our case.
| Conclusions|| |
Although advanced PPC showed a poor response to chemotherapy, our patient with an EGFR mutation achieved an excellent partial response. We therefore recommend the evaluation of driver gene alteration such as EGFR in the treatment of advanced PPC.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Chang YL, Lee YC, Shih JY, Wu CT. Pulmonary pleomorphic (spindle) cell carcinoma: Peculiar clinicopathologic manifestations different from ordinary non-small cell carcinoma. Lung Cancer 2001;34:91-7.
Travis WD. Pathology of lung cancer. Clin Chest Med 2002;23:65-81, viii.
Brambilla E, Travis WD, Colby TV, Corrin B, Shimosato Y. The new world health organization classification of lung tumours. Eur Respir J 2001;18:1059-68.
Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC. World Health Organization Classification of Tumors: Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. Lyon: IARC Press; 2004:p. 53-8.
Fishback NF, Travis WD, Moran CA, Guinee DG Jr., McCarthy WF, Koss MN. Pleomorphic (spindle/giant cell) carcinoma of the lung. A clinicopathologic correlation of 78 cases. Cancer 1994;73:2936-45.
Rossi G, Cavazza A, Sturm N, Migaldi M, Facciolongo N, Longo L, et al.
Pulmonary carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements: A clinicopathologic and immunohistochemical study of 75 cases. Am J Surg Pathol 2003;27:311-24.
Mochizuki T, Ishii G, Nagai K, Yoshida J, Nishimura M, Mizuno T, et al.
Pleomorphic carcinoma of the lung: Clinicopathologic characteristics of 70 cases. Am J Surg Pathol 2008;32:1727-35.
Mitsudomi T, Yatabe Y. Mutations of the epidermal growth factor receptor gene and related genes as determinants of epidermal growth factor receptor tyrosine kinase inhibitors sensitivity in lung cancer. Cancer Sci 2007;98:1817-24.
Ishida T, Tateishi M, Kaneko S, Yano T, Mitsudomi T, Sugimachi K, et al.
Carcinosarcoma and spindle cell carcinoma of the lung. Clinicopathologic and immunohistochemical studies. J Thorac Cardiovasc Surg 1990;100:844-52.
Addis BJ, Corrin B. Pulmonary blastoma, carcinosarcoma and spindle-cell carcinoma: An immunohistochemical study of keratin intermediate filaments. J Pathol 1985;147:291-301.
Yoshino N, Kubokura H, Yamauchi S, Ohaki Y, Koizumi K, Shimizu K. Atrue pulmonary carcinosarcoma that required diagnostic differentiation from a pleomorphic adenoma: A case report. Ann Thorac Cardiovasc Surg 2009;15:42-5.
Bae HM, Min HS, Lee SH, Kim DW, Chung DH, Lee JS, et al.
Palliative chemotherapy for pulmonary pleomorphic carcinoma. Lung Cancer 2007;58:112-5.
Hong JY, Choi MK, Uhm JE, Park MJ, Lee J, Park YH, et al.
The role of palliative chemotherapy for advanced pulmonary pleomorphic carcinoma. Med Oncol 2009;26:287-91.
Tamiya A, Asami K, Shimizu S, Matsumura A, Isa S, Okishio K, et al.
Long-term complete response in a patient with disseminated pulmonary pleomorphic carcinoma induced by cisplatin and gemcitabine. Intern Med 2014;53:2625-8.
Tamura Y, Fujiwara Y, Yamamoto N, Nokihara H, Horinouchi H, Kanda S, et al.
Retrospective analysis of the efficacy of chemotherapy and molecular targeted therapy for advanced pulmonary pleomorphic carcinoma. BMC Res Notes 2015;8:800.
Azzoli CG, Temin S, Aliff T, Baker S Jr., Brahmer J, Johnson DH, et al.
2011 focused update of 2009 American society of clinical oncology clinical practice guideline update on chemotherapy for stage IV non-small-cell lung cancer. J Clin Oncol 2011;29:3825-31.
Reck M, Popat S, Reinmuth N, De Ruysscher D, Kerr KM, Peters S, et al.
Metastatic non-small-cell lung cancer (NSCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2014;25 Suppl 3:iii27-39.
Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, et al.
First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N
Engl J Med 2014;371:2167-77.
Ito K, Oizumi S, Fukumoto S, Harada M, Ishida T, Fujita Y, et al.
Clinical characteristics of pleomorphic carcinoma of the lung. Lung Cancer 2010;68:204-10.
Kaira K, Horie Y, Ayabe E, Murakami H, Takahashi T, Tsuya A, et al.
Pulmonary pleomorphic carcinoma: A clinicopathological study including EGFR mutation analysis. J Thorac Oncol 2010;5:460-5.
Ushiki A, Koizumi T, Kobayashi N, Kanda S, Yasuo M, Yamamoto H, et al.
Genetic heterogeneity of EGFR mutation in pleomorphic carcinoma of the lung: Response to gefitinib and clinical outcome. Jpn J Clin Oncol 2009;39:267-70.
Saitoh M, Niijima M, Takiguchi Y, Hiroshima K, Fujita Y, Nishio K, et al.
An early event of EGFR mutation in pleomorphic carcinoma of the lung. Int J Clin Oncol 2011;16:770-3.
Lee S, Kim Y, Sun JM, Choi YL, Kim JG, Shim YM, et al.
Molecular profiles of EGFR, K-ras, c-met, and FGFR in pulmonary pleomorphic carcinoma, a rare lung malignancy. J Cancer Res Clin Oncol 2011;137:1203-11.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]