- Email: [email protected]
An unusual recurrence of adenosquamous carcinoma of the lung
Cancer Treatment Communications (2015) 4, 37–40
An unusual recurrence of adenosquamous carcinoma of the lung Khageshwor Pokharela,b, David Godboltc, Brett G.M. Hughesb,c,d,n a
Princess Alexandra Hospital, Woolloongabba, Queensland, Australia School of Medicine, University of Queensland, St Lucia, Queensland, Australia c The Prince Charles Hospital, Chermside, Queensland, Australia d The Royal Brisbane and Women's Hospital, Herston, Queensland, Australia b
Received 24 December 2014; received in revised form 27 March 2015; accepted 28 March 2015
1.
KEYWORDS
Abstract
Non-small cell lung cancer; Adenosquamous; EGFR mutation; Histology discordance
Adenosquamous carcinoma of the lung is an uncommon histological variant of non-small cell lung carcinoma (NSCLC) associated with a poorer prognosis than either adenocarcinoma or squamous cell carcinoma (SCC) histological subtypes. Most adenosquamous carcinomas of the lung present with advanced disease, often with the central nervous system as a common site of metastasis. We present a case of a patient with recurrent adenosquamous carcinoma who presents with multiple cerebral metastases, with two metastatic sites composed of separate distinct histological subtypes, one adenocarcinoma and one SCC. Interestingly, both metastatic deposits were also found to harbor an L858R epithelial growth factor receptor (EGFR) point mutation in exon 21. Upon progression after craniotomy and whole brain radiotherapy, the patient achieved a radiological response with the EGFR inhibitor, erlotinib. Crown Copyright & 2015 Published by Elsevier Ltd. All rights reserved.
Introduction
Lung cancer remains the most common cause of cancer death due to late presentation with advanced disease in the majority of cases. Mixed histology primary non-small cell lung cancer (NSCLC) is rare, although adenosquamous carcinoma represents the commonest subtype within this histological group, representing 0.4–4% of cases [1]. According to World Health n
Corresponding author at: The Prince Charles Hospital, Chermside, Queensland, Australia. E-mail address: [email protected] (B.G.M. Hughes).
Organisation's classification, adenosquamous carcinoma is defined as a carcinoma showing components of both adenocarcinoma and squamous cell carcinoma (SCC), with each component comprising at least 10% of the tumor [2]. Survival rates remain poor despite surgical resection in early stage disease compared to staged-matched NSCLC cases with a high preponderance for cerebral metastasis as a site of distant recurrence [3]. The incidence of separate histological phenotype in cerebral metastasis of adenosquamous carcinoma has not been previously reported and we describe a case of this unusual pattern of recurrence. A 65 year old male initially presented with chest pain in September 2010. He had a remote smoking history of 4 pack
http://dx.doi.org/10.1016/j.ctrc.2015.03.006 2213-0896/Crown Copyright & 2015 Published by Elsevier Ltd. All rights reserved.
38 years of smoking and had quit 43 years earlier. Investigation with a chest x-ray revealed 58 mm left upper lobe mass. Endobronchial biopsy demonstrated NSCLC. Complete staging with computer tomography (CT) and 18-Fludeoxyglucose Positron Emission Tomography (FDG-PET) revealed no nodal or distant metastatic disease and he proceeded to definitive left upper lobectomy. Thorough histopathological examination revealed an adenosquamous variant of NSCLC with the adenocarcinoma component positive for thyroid transcription factor 1 (TTF-1) and CK7 representing 30% of the total specimen and the SCC component positive for p63 and CK5/ 6 and negative for TTF1 and CK7 representing the remaining 70% of the tumour (Figure 1). The tumour measured 60 mm and invaded the visceral pleura with extensive lymphovascular invasion. There were peribronchial and left hilar lymph node involvement with metastatic disease resulting in a pathological stage of pT2bN1M0. Post-operatively, he received four courses of adjuvant cisplatin (50 mg/m2 day 1 and 8) and vinorelbine (25 mg/m2 day 1, 8 and 15) every 4 weeks completed by March 2011. Ten months later (January 2012) he was found to have a left paratracheal and aorto-pulmonary nodal recurrence on routine follow-up CT imaging. This was confirmed with a transbronchial nodal biopsy with histological examination demonstrating recurrent SCC. FDG–PET did not reveal any extrathoracic metastasis. Subsequent imaging of the brain with CT and magnetic resonance imaging (MRI) scan (Figure 2) demonstrated three cerebral metastases, two in the left frontal lobe (26 43 mm and 19 14 mm) with 8 mm midline shift and one in right frontal lobe (15 7 mm) complicated by new onset of generalised seizures requiring levetiracetum. The patient subsequently then underwent a craniotomy and resection of the two left frontal lobe metastases. Thorough histological assessment of both metastases interestingly demonstrated two distinct histological subtypes, one adenocarcinoma and the other SCC, both with distinct cytokeratin profiles consistent with the differing histological morphologies. Furthermore, the both metastatic deposits
Figure 1 Histology of the adenosquamous carcinoma of the lung. The brown chromogen stains thyroid transcription factor 1 (TTF-1) representing the adenocarcinoma component. The red chromogen stains CK5/6 representing the squamous cell carcinoma component.
K. Pokharel et al.
Figure 2 Magnetic resonance imaging of the brain (T1 weighted images post gadolinium contrast) demonstrating two cerebral metastases. The adenocarcinoma metastasis is the solid anterior lesion and the squamous metastasis the posterior cystic lesion.
were found to harbor a L858R epithelial growth factor receptor (EGFR) point mutation in exon 21. He received post-operative whole brain radiation to a dose of 30 Gy in ten fractions [4,5]. Unfortunately, subsequent imaging after completion of whole brain radiotherapy revealed further progression of the contralateral right frontal lobe lesion which now measured 32 22 mm (compared to 15 7 mm previously) and evidence of residual disease in the surgical frontal lobe cavity. Erlotinib was commenced in an attempt to adequately treat both the systemic and CNS disease based on data from various studies [6–9]. Erlotinib was generally well tolerated with grade II acneform rash and diarrhoea requiring the addition of doxycyline 100 mg bd and loperamide for management of these adverse effects with good effect. Follow up imaging with whole body CT scan and MRI of the brain initially demonstrated both a response to his intracerebral and mediastinal nodal disease without evidence of new distant metastasis. Due to subsequent slow progression of the CNS metastases, the patient subsequently underwent a redocraniotomy for the disease in the left frontal lobe followed by further whole brain radiotherapy to an additional dose of 20 Gy in 10 fractions. Repeat mutational analysis was not performed and the patient remained on erlotinib for 24 months with follow up imaging demonstrating further minor progression of his left frontal lobe disease, stable disease in the mediastinal nodal disease and the appearance of asymptomatic bony metastases in lumbar vertebra 3 and 4. After further clinical and radiological deterioration, and increase frequency of complex partial seizure despite escalating doses of levetiracetum, the patient died in April 2014, 27 months after the initial development of multiple cerebral metastases.
An unusual recurrence of adenosquamous carcinoma
2.
Discussion
Adenosquamous lung cancer is an aggressive subtype of NSCLC with a poor long term prognosis. Its pathogenesis poorly understood, this disease is thought to arise from single clone of mutated cells. This single clone of cells, in the multistep process of tumorigenesis, acquires different protein expressions resulting in the cells differentiating into two different distinct phenotypes [10]. Whilst these two different phenotypes coexist initially, when invasion and metastasis occur, they may theoretically present as two separate entities but have similar oncogenic driver mutations. This was also highlighted by Paik et. al. [11] in their case series from the Memorial Sloan Kettering where they reported 13 cases of confirmed adenosquamous lung carcinomas with EGFR mutations on review of the original pathology that had been originally reported as pure SCC in at least one sample. All of these patients were treated with erlotinib with a reported overall response rate (ORR) of 88% and a median progression free survival (PFS) of 12 months. These figures are similar to that seen in pure adenocarcinomas harbouring an activating EGFR mutation [12]. As in our case, these tumours may be incorrectly characterised as pure SCC in small histological samples at recurrence. Caution should be undertaken when interpreting these small histological samples as they may not be representative of the whole tumour and reinforces the need for adequate sampling to guide therapeutic decisions. Previous reports had suggested that ORR to EGFR tyrosine kinase inhibitors in Asian patients with EGFR mutant SCC were approximately half of that seen in adenocarcinomas with a corresponding shorter PFS of 4–5 months [13]. These outcomes are similar to that seen in treatment naive patients with platinum based doublet chemotherapy. Whether this holds true in general for Caucasian patients or in tumours of mixed histology is unclear. This case reports the unique occurrence of two distinct cerebral metastases of different histological subtype from the one single tumour. To our knowledge, no such case is reported in literature and this occurrence highlights the complexity of management of metastatic adenosquamous lung cancer, particularly in the presence of an oncogenic driver mutation, such as was found in exon 21 of EGFR in this case. As additional oncogencic targets are identified in adenocarcinomas [12], management of adenosquamous as a single entity is likely to also become more challenging. The frequency of oncogenic driver mutation such as EGFR or KRAS appears similar to pure adenocarcinomas [14] with similar mutations found in both adenocarcinoma and SCC components [15]. With the increasing knowledge of acquired resistance mechanisms to EGFR tyrosine kinase inhibitors, mainly due to the emergence of T790M as the dominant resistance pathway seen in 50–60% of cases [12], consideration of repeat mutational analysis is important to further individualise patient therapy. Highly potent, mutant selective, third generation EGFR inhibitors that block T790M, such as AZD9291 [16] and CO-1686 [17], have now demonstrated significant activity in this situation. Unfortunately, due to the lack of availability of these drugs at the time of our patient's progression, repeat mutational analysis was not
39 performed in this case. This would remain however an important consideration in the management of such a patient in the future with the increasing availability of these drugs and other similar third generation EGFR inhibitors. Due to its low incidence and uncertain biology, there remain no separate guidelines for the management of adenosquamous lung carcinomas and as such, they are treated in accordance with standard NSCLC practice guidelines [18]. Although there is growing evidence that such tumours may harbour “druggable” oncogenic driver mutations at a similar frequency to non-squamous NSCLC, and when these mutations are present may demonstrate a similar sensitivity to EGFR tyrosine kinase inhibitors, they may still not routinely be subjected to molecular analysis [19,20]. Recently however, international bodies such as the International Association for the Study of Lung Cancer (IASLC) and the American Thoracic Society have recommended routine molecular testing for these tumours also. The benefits of this approach if a sensitising EGFR is detected are highlighted in this report. The unusual pattern of recurrence seen in this case underscores the need for thorough histological evaluation in metastatic setting for both prognostic and therapeutic reasons, particularly in an era of available molecular targeted therapies. It also raises the potential role of EGFR tyrosine kinase inhibitors in cerebral metastasis harbouring an activating mutation.
3.
Conclusion
This case highlights the unusual biological behaviour of adenosquamous lung cancer leading to metastases of two different histological phenotypes. It is also noteworthy that the frequency of EGFR activating mutations in metastatic adenosquamous lung cancer and the sensitivity of EGFR tyrosine kinase inhibitors when these mutations are present appear similar to pure adenocarcinomas. For these reasons, precise thorough histological characterisation with adequate tumour sampling and EGFR mutational analysis remain important components of the investigation and management of patients with adenosquamous carcinomas of the lung.
Conflict of interest BH is an Advisory Board member with Roche; KP and DG have no disclosures to declare.
Clinical practice points
Adenosquamous carcinoma of the lung is an uncommon
histological variant of non-small cell lung carcinoma (NSCLC) associated with a poorer prognosis than either adenocarcinoma or squamous cell carcinoma (SCC) histological subtypes with the central nervous system (CNS) as a common site of metastasis. This case reports a patient with recurrent adenosquamous carcinoma who presents with multiple cerebral metastases, with two metastatic sites composed of separate distinct histological subtypes, one adenocarcinoma and
40
K. Pokharel et al. one SCC – a phenomenon not previously reported in the literature. Furthermore, both CNS metastatic deposits were also found to harbor an L858R epithelial growth factor receptor (EGFR) point mutation in exon 21. Upon progression after craniotomy and whole brain radiotherapy, the patient achieved a radiological response with the EGFR inhibitor, erlotinib. Mutational analysis for EGFR should be performed in all cases of adenosquamous lung carcinoma.
[10]
[11]
[12]
References [1] E. Ruffini, O. Rena, A. Oliaro, P.L. Filosso, M. Bongiovanni, A. Arslanian, E. Papalia, G. Maggi, Lung tumors with mixed histologic pattern. Clinico-pathologic characteristics and prognostic significance, Eur. J. Cardiothorac. Surg. 22 (5) (2002) 701–707. [2] W.D. Travis, E. Branbilla, H.K. Muller-Hermelink, H.H. Harris, World Health Organisation Classification of tumors. Pathology of tumors of lung, pleura, thymus and heart, IARC, Lyon10–52. [3] P.L. Filosso, E. Ruffini, S. Asioli, R. Giobbe, L. Macri, M. C. Bruna, A. Sandri, A. Oliaro, Adenosquamous lung carcinomas: a histologic subtype with poor prognosis, Lung Cancer 74 (1) (2011) 25–29. [4] D.W. Andrews, C.B. Scott, P.W. Sperduto, A.E. Flanders, L. E. Gaspar, M.C. Schell, M. Werner-Wasik, W. Demas, J. Ryu, J. P. Bahary, L. Souhami, M. Rotman, M.P. Mehta, W.J. Curran Jr, Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial, Lancet 363 (9422) (2004) 1665–1672. [5] T. Mekhail, M. Sombeck, R. Sollaccio, Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of 1-3 cerebral metastases: results of the EORTC 22952-26001 study, Curr. Oncol. Rep. 13 (4) (2011) 255–258. [6] F. Cappuzzo, A. Ardizzoni, H. Soto-Parra, et al., Epidermal growth factor receptor targeted therapy by ZD 1839 (Iressa) in patients with brain metastases from non-small cell lung cancer (NSCLC), Lung Cancer 41 (2) (2003) 227–231. [7] H. Takahashi, T. Ohrui, S. Ebihara, M. Yamada, H. Sasaki, Effect of gefitinib (ZD1839) on metastatic brain tumour, Lung Cancer 43 (3) (2004) 371–372. [8] M.H. Fekrazad, M. Ravindranathan, D.V. Jones Jr., Response of intracranial metastases to erlotinib therapy, J. Clin. Oncol. 25 (31) (2007) 5024–5026. [9] G.L. Ceresoli, F. Cappuzzo, V. Gregorc, S. Bartolini, L. Crinò, E. Villa, Gefitinib in patients with brain metastases from non-
[13]
[14]
[15]
[16]
[17]
[18] [19]
[20]
small-cell lung cancer: a prospective trial, Ann. Oncol. 15 (7) (2004) 1042–1047. S. Toyooka, Y. Yatabe, M. Tokumo, K. Ichimura, H. Asan, K. Tomii, M. Aoe, H. Yanai, Hiroshi Date, T. Mitsudomi, N. Shimizu, Mutations of epidermal growth factor receptor and K-ras genes in adenosquamous carcinoma of the lung, Int. J. Cancer 118 (2006) 1588–1590. P.K. Paik, A.M. Varghese, C.S. Sima, A.L. Moreira, M. Ladanyi, M.G. Kris, N. Rekhtman, Response to erlotinib in patients with EGFR mutant advanced non-small cell lung cancers with a squamous or squamous-like component, Mol. Cancer Ther. 11 (11) (2012) 2535–2540. B. Chan, B. Hughes, Targeted therapy for non-small cell lung cancer: current standards and the promise of the future, Transl. Lung Cancer Res. 4 (1) (2014) 36–54. C.H.1 Chiu, T.Y. Chou, C.L. Chiang, C.M. Tsai, Should EGFR mutations be tested in advanced lung squamous cell carcinomas to guide frontline treatment? Cancer Chemother. Pharmacol. 74 (4) (2014 Oct) 661–665. http://dx.doi.org/10.1007/ s00280-014-2536-3. T. Naobumi, D. Sanja, N. Marina, K. Cieply, S. Yousem, Adenosquamous carcinoma of the lung. a microdissection study of KRAS and EGFR mutational and amplification status in a western patient population, Am. J. Clin. Pathol. 135 (2011) 783–789. S.M. Kang, H.J. Kang, J.H. Shin, et al., Identical epidermal growth factor receptor mutations in adenocarcinomatous and squamous cell carcinomatous components of adenosquamous carcinoma of the lung, Cancer 109 (2007) 581–587. P. Janne, S. Ramalingam, J. Yang, M. Ahn, D. Kim, S. Kim, et al., Clinical activity of the mutant-selective EGFR inhibitor AZD9291 in patients (pts) with EGFR inhibitor-resistant nonsmall cell lung cancer (NSCLC), J. Clin. Oncol. 32 (2014) 5s (suppl; abstr 8009). L. Sequist, J. Soria, S. Gadgeel, H. Wakelee, R. Camidge, A. Varga, et al., First-in-human evaluation of CO-1686, an irreversible, highly selective tyrosine kinase inhibitor of mutations of EGFR (activating and T790M), J. Clin. Oncol. 32 (2014) 5s (suppl; abstr 8010). NCCN guidelines for management of NSCLC. Version 4, 2014. R. Wang, Y. Pan, C. Li, H. Zhang, D. Garfield, Y. Li, T. Ye, H. Hu, X. Luo, H. Li, Y. Zhang, J. Zhang, X. Zhou, L. Shen, W. Pao, Y. Sun, H. Chen, Analysis of major known driver mutations and prognosis in resected adenosquamous lung carcinomas, J. Thorac. Oncol. 9 (2014) 760–768. Z. Song, B. Lin, L. Shao, Y. Zhang, Therapeutic efficacy of gefitinib and erlotinib in patients with advanced lung adenosquamous carcinoma, J. Chin. Med. Assoc. 76 (9) (2013) 481–485, http://dx.doi.org/10.1016/j.jcma.2013.05.007 Epub 2013; Jun 13.
An unusual recurrence of adenosquamous carcinoma of the lung Khageshwor Pokharela,b, David Godboltc, Brett G.M. Hughesb,c,d,n a
Princess Alexandra Hospital, Woolloongabba, Queensland, Australia School of Medicine, University of Queensland, St Lucia, Queensland, Australia c The Prince Charles Hospital, Chermside, Queensland, Australia d The Royal Brisbane and Women's Hospital, Herston, Queensland, Australia b
Received 24 December 2014; received in revised form 27 March 2015; accepted 28 March 2015
1.
KEYWORDS
Abstract
Non-small cell lung cancer; Adenosquamous; EGFR mutation; Histology discordance
Adenosquamous carcinoma of the lung is an uncommon histological variant of non-small cell lung carcinoma (NSCLC) associated with a poorer prognosis than either adenocarcinoma or squamous cell carcinoma (SCC) histological subtypes. Most adenosquamous carcinomas of the lung present with advanced disease, often with the central nervous system as a common site of metastasis. We present a case of a patient with recurrent adenosquamous carcinoma who presents with multiple cerebral metastases, with two metastatic sites composed of separate distinct histological subtypes, one adenocarcinoma and one SCC. Interestingly, both metastatic deposits were also found to harbor an L858R epithelial growth factor receptor (EGFR) point mutation in exon 21. Upon progression after craniotomy and whole brain radiotherapy, the patient achieved a radiological response with the EGFR inhibitor, erlotinib. Crown Copyright & 2015 Published by Elsevier Ltd. All rights reserved.
Introduction
Lung cancer remains the most common cause of cancer death due to late presentation with advanced disease in the majority of cases. Mixed histology primary non-small cell lung cancer (NSCLC) is rare, although adenosquamous carcinoma represents the commonest subtype within this histological group, representing 0.4–4% of cases [1]. According to World Health n
Corresponding author at: The Prince Charles Hospital, Chermside, Queensland, Australia. E-mail address: [email protected] (B.G.M. Hughes).
Organisation's classification, adenosquamous carcinoma is defined as a carcinoma showing components of both adenocarcinoma and squamous cell carcinoma (SCC), with each component comprising at least 10% of the tumor [2]. Survival rates remain poor despite surgical resection in early stage disease compared to staged-matched NSCLC cases with a high preponderance for cerebral metastasis as a site of distant recurrence [3]. The incidence of separate histological phenotype in cerebral metastasis of adenosquamous carcinoma has not been previously reported and we describe a case of this unusual pattern of recurrence. A 65 year old male initially presented with chest pain in September 2010. He had a remote smoking history of 4 pack
http://dx.doi.org/10.1016/j.ctrc.2015.03.006 2213-0896/Crown Copyright & 2015 Published by Elsevier Ltd. All rights reserved.
38 years of smoking and had quit 43 years earlier. Investigation with a chest x-ray revealed 58 mm left upper lobe mass. Endobronchial biopsy demonstrated NSCLC. Complete staging with computer tomography (CT) and 18-Fludeoxyglucose Positron Emission Tomography (FDG-PET) revealed no nodal or distant metastatic disease and he proceeded to definitive left upper lobectomy. Thorough histopathological examination revealed an adenosquamous variant of NSCLC with the adenocarcinoma component positive for thyroid transcription factor 1 (TTF-1) and CK7 representing 30% of the total specimen and the SCC component positive for p63 and CK5/ 6 and negative for TTF1 and CK7 representing the remaining 70% of the tumour (Figure 1). The tumour measured 60 mm and invaded the visceral pleura with extensive lymphovascular invasion. There were peribronchial and left hilar lymph node involvement with metastatic disease resulting in a pathological stage of pT2bN1M0. Post-operatively, he received four courses of adjuvant cisplatin (50 mg/m2 day 1 and 8) and vinorelbine (25 mg/m2 day 1, 8 and 15) every 4 weeks completed by March 2011. Ten months later (January 2012) he was found to have a left paratracheal and aorto-pulmonary nodal recurrence on routine follow-up CT imaging. This was confirmed with a transbronchial nodal biopsy with histological examination demonstrating recurrent SCC. FDG–PET did not reveal any extrathoracic metastasis. Subsequent imaging of the brain with CT and magnetic resonance imaging (MRI) scan (Figure 2) demonstrated three cerebral metastases, two in the left frontal lobe (26 43 mm and 19 14 mm) with 8 mm midline shift and one in right frontal lobe (15 7 mm) complicated by new onset of generalised seizures requiring levetiracetum. The patient subsequently then underwent a craniotomy and resection of the two left frontal lobe metastases. Thorough histological assessment of both metastases interestingly demonstrated two distinct histological subtypes, one adenocarcinoma and the other SCC, both with distinct cytokeratin profiles consistent with the differing histological morphologies. Furthermore, the both metastatic deposits
Figure 1 Histology of the adenosquamous carcinoma of the lung. The brown chromogen stains thyroid transcription factor 1 (TTF-1) representing the adenocarcinoma component. The red chromogen stains CK5/6 representing the squamous cell carcinoma component.
K. Pokharel et al.
Figure 2 Magnetic resonance imaging of the brain (T1 weighted images post gadolinium contrast) demonstrating two cerebral metastases. The adenocarcinoma metastasis is the solid anterior lesion and the squamous metastasis the posterior cystic lesion.
were found to harbor a L858R epithelial growth factor receptor (EGFR) point mutation in exon 21. He received post-operative whole brain radiation to a dose of 30 Gy in ten fractions [4,5]. Unfortunately, subsequent imaging after completion of whole brain radiotherapy revealed further progression of the contralateral right frontal lobe lesion which now measured 32 22 mm (compared to 15 7 mm previously) and evidence of residual disease in the surgical frontal lobe cavity. Erlotinib was commenced in an attempt to adequately treat both the systemic and CNS disease based on data from various studies [6–9]. Erlotinib was generally well tolerated with grade II acneform rash and diarrhoea requiring the addition of doxycyline 100 mg bd and loperamide for management of these adverse effects with good effect. Follow up imaging with whole body CT scan and MRI of the brain initially demonstrated both a response to his intracerebral and mediastinal nodal disease without evidence of new distant metastasis. Due to subsequent slow progression of the CNS metastases, the patient subsequently underwent a redocraniotomy for the disease in the left frontal lobe followed by further whole brain radiotherapy to an additional dose of 20 Gy in 10 fractions. Repeat mutational analysis was not performed and the patient remained on erlotinib for 24 months with follow up imaging demonstrating further minor progression of his left frontal lobe disease, stable disease in the mediastinal nodal disease and the appearance of asymptomatic bony metastases in lumbar vertebra 3 and 4. After further clinical and radiological deterioration, and increase frequency of complex partial seizure despite escalating doses of levetiracetum, the patient died in April 2014, 27 months after the initial development of multiple cerebral metastases.
An unusual recurrence of adenosquamous carcinoma
2.
Discussion
Adenosquamous lung cancer is an aggressive subtype of NSCLC with a poor long term prognosis. Its pathogenesis poorly understood, this disease is thought to arise from single clone of mutated cells. This single clone of cells, in the multistep process of tumorigenesis, acquires different protein expressions resulting in the cells differentiating into two different distinct phenotypes [10]. Whilst these two different phenotypes coexist initially, when invasion and metastasis occur, they may theoretically present as two separate entities but have similar oncogenic driver mutations. This was also highlighted by Paik et. al. [11] in their case series from the Memorial Sloan Kettering where they reported 13 cases of confirmed adenosquamous lung carcinomas with EGFR mutations on review of the original pathology that had been originally reported as pure SCC in at least one sample. All of these patients were treated with erlotinib with a reported overall response rate (ORR) of 88% and a median progression free survival (PFS) of 12 months. These figures are similar to that seen in pure adenocarcinomas harbouring an activating EGFR mutation [12]. As in our case, these tumours may be incorrectly characterised as pure SCC in small histological samples at recurrence. Caution should be undertaken when interpreting these small histological samples as they may not be representative of the whole tumour and reinforces the need for adequate sampling to guide therapeutic decisions. Previous reports had suggested that ORR to EGFR tyrosine kinase inhibitors in Asian patients with EGFR mutant SCC were approximately half of that seen in adenocarcinomas with a corresponding shorter PFS of 4–5 months [13]. These outcomes are similar to that seen in treatment naive patients with platinum based doublet chemotherapy. Whether this holds true in general for Caucasian patients or in tumours of mixed histology is unclear. This case reports the unique occurrence of two distinct cerebral metastases of different histological subtype from the one single tumour. To our knowledge, no such case is reported in literature and this occurrence highlights the complexity of management of metastatic adenosquamous lung cancer, particularly in the presence of an oncogenic driver mutation, such as was found in exon 21 of EGFR in this case. As additional oncogencic targets are identified in adenocarcinomas [12], management of adenosquamous as a single entity is likely to also become more challenging. The frequency of oncogenic driver mutation such as EGFR or KRAS appears similar to pure adenocarcinomas [14] with similar mutations found in both adenocarcinoma and SCC components [15]. With the increasing knowledge of acquired resistance mechanisms to EGFR tyrosine kinase inhibitors, mainly due to the emergence of T790M as the dominant resistance pathway seen in 50–60% of cases [12], consideration of repeat mutational analysis is important to further individualise patient therapy. Highly potent, mutant selective, third generation EGFR inhibitors that block T790M, such as AZD9291 [16] and CO-1686 [17], have now demonstrated significant activity in this situation. Unfortunately, due to the lack of availability of these drugs at the time of our patient's progression, repeat mutational analysis was not
39 performed in this case. This would remain however an important consideration in the management of such a patient in the future with the increasing availability of these drugs and other similar third generation EGFR inhibitors. Due to its low incidence and uncertain biology, there remain no separate guidelines for the management of adenosquamous lung carcinomas and as such, they are treated in accordance with standard NSCLC practice guidelines [18]. Although there is growing evidence that such tumours may harbour “druggable” oncogenic driver mutations at a similar frequency to non-squamous NSCLC, and when these mutations are present may demonstrate a similar sensitivity to EGFR tyrosine kinase inhibitors, they may still not routinely be subjected to molecular analysis [19,20]. Recently however, international bodies such as the International Association for the Study of Lung Cancer (IASLC) and the American Thoracic Society have recommended routine molecular testing for these tumours also. The benefits of this approach if a sensitising EGFR is detected are highlighted in this report. The unusual pattern of recurrence seen in this case underscores the need for thorough histological evaluation in metastatic setting for both prognostic and therapeutic reasons, particularly in an era of available molecular targeted therapies. It also raises the potential role of EGFR tyrosine kinase inhibitors in cerebral metastasis harbouring an activating mutation.
3.
Conclusion
This case highlights the unusual biological behaviour of adenosquamous lung cancer leading to metastases of two different histological phenotypes. It is also noteworthy that the frequency of EGFR activating mutations in metastatic adenosquamous lung cancer and the sensitivity of EGFR tyrosine kinase inhibitors when these mutations are present appear similar to pure adenocarcinomas. For these reasons, precise thorough histological characterisation with adequate tumour sampling and EGFR mutational analysis remain important components of the investigation and management of patients with adenosquamous carcinomas of the lung.
Conflict of interest BH is an Advisory Board member with Roche; KP and DG have no disclosures to declare.
Clinical practice points
Adenosquamous carcinoma of the lung is an uncommon
histological variant of non-small cell lung carcinoma (NSCLC) associated with a poorer prognosis than either adenocarcinoma or squamous cell carcinoma (SCC) histological subtypes with the central nervous system (CNS) as a common site of metastasis. This case reports a patient with recurrent adenosquamous carcinoma who presents with multiple cerebral metastases, with two metastatic sites composed of separate distinct histological subtypes, one adenocarcinoma and
40
K. Pokharel et al. one SCC – a phenomenon not previously reported in the literature. Furthermore, both CNS metastatic deposits were also found to harbor an L858R epithelial growth factor receptor (EGFR) point mutation in exon 21. Upon progression after craniotomy and whole brain radiotherapy, the patient achieved a radiological response with the EGFR inhibitor, erlotinib. Mutational analysis for EGFR should be performed in all cases of adenosquamous lung carcinoma.
[10]
[11]
[12]
References [1] E. Ruffini, O. Rena, A. Oliaro, P.L. Filosso, M. Bongiovanni, A. Arslanian, E. Papalia, G. Maggi, Lung tumors with mixed histologic pattern. Clinico-pathologic characteristics and prognostic significance, Eur. J. Cardiothorac. Surg. 22 (5) (2002) 701–707. [2] W.D. Travis, E. Branbilla, H.K. Muller-Hermelink, H.H. Harris, World Health Organisation Classification of tumors. Pathology of tumors of lung, pleura, thymus and heart, IARC, Lyon10–52. [3] P.L. Filosso, E. Ruffini, S. Asioli, R. Giobbe, L. Macri, M. C. Bruna, A. Sandri, A. Oliaro, Adenosquamous lung carcinomas: a histologic subtype with poor prognosis, Lung Cancer 74 (1) (2011) 25–29. [4] D.W. Andrews, C.B. Scott, P.W. Sperduto, A.E. Flanders, L. E. Gaspar, M.C. Schell, M. Werner-Wasik, W. Demas, J. Ryu, J. P. Bahary, L. Souhami, M. Rotman, M.P. Mehta, W.J. Curran Jr, Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial, Lancet 363 (9422) (2004) 1665–1672. [5] T. Mekhail, M. Sombeck, R. Sollaccio, Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of 1-3 cerebral metastases: results of the EORTC 22952-26001 study, Curr. Oncol. Rep. 13 (4) (2011) 255–258. [6] F. Cappuzzo, A. Ardizzoni, H. Soto-Parra, et al., Epidermal growth factor receptor targeted therapy by ZD 1839 (Iressa) in patients with brain metastases from non-small cell lung cancer (NSCLC), Lung Cancer 41 (2) (2003) 227–231. [7] H. Takahashi, T. Ohrui, S. Ebihara, M. Yamada, H. Sasaki, Effect of gefitinib (ZD1839) on metastatic brain tumour, Lung Cancer 43 (3) (2004) 371–372. [8] M.H. Fekrazad, M. Ravindranathan, D.V. Jones Jr., Response of intracranial metastases to erlotinib therapy, J. Clin. Oncol. 25 (31) (2007) 5024–5026. [9] G.L. Ceresoli, F. Cappuzzo, V. Gregorc, S. Bartolini, L. Crinò, E. Villa, Gefitinib in patients with brain metastases from non-
[13]
[14]
[15]
[16]
[17]
[18] [19]
[20]
small-cell lung cancer: a prospective trial, Ann. Oncol. 15 (7) (2004) 1042–1047. S. Toyooka, Y. Yatabe, M. Tokumo, K. Ichimura, H. Asan, K. Tomii, M. Aoe, H. Yanai, Hiroshi Date, T. Mitsudomi, N. Shimizu, Mutations of epidermal growth factor receptor and K-ras genes in adenosquamous carcinoma of the lung, Int. J. Cancer 118 (2006) 1588–1590. P.K. Paik, A.M. Varghese, C.S. Sima, A.L. Moreira, M. Ladanyi, M.G. Kris, N. Rekhtman, Response to erlotinib in patients with EGFR mutant advanced non-small cell lung cancers with a squamous or squamous-like component, Mol. Cancer Ther. 11 (11) (2012) 2535–2540. B. Chan, B. Hughes, Targeted therapy for non-small cell lung cancer: current standards and the promise of the future, Transl. Lung Cancer Res. 4 (1) (2014) 36–54. C.H.1 Chiu, T.Y. Chou, C.L. Chiang, C.M. Tsai, Should EGFR mutations be tested in advanced lung squamous cell carcinomas to guide frontline treatment? Cancer Chemother. Pharmacol. 74 (4) (2014 Oct) 661–665. http://dx.doi.org/10.1007/ s00280-014-2536-3. T. Naobumi, D. Sanja, N. Marina, K. Cieply, S. Yousem, Adenosquamous carcinoma of the lung. a microdissection study of KRAS and EGFR mutational and amplification status in a western patient population, Am. J. Clin. Pathol. 135 (2011) 783–789. S.M. Kang, H.J. Kang, J.H. Shin, et al., Identical epidermal growth factor receptor mutations in adenocarcinomatous and squamous cell carcinomatous components of adenosquamous carcinoma of the lung, Cancer 109 (2007) 581–587. P. Janne, S. Ramalingam, J. Yang, M. Ahn, D. Kim, S. Kim, et al., Clinical activity of the mutant-selective EGFR inhibitor AZD9291 in patients (pts) with EGFR inhibitor-resistant nonsmall cell lung cancer (NSCLC), J. Clin. Oncol. 32 (2014) 5s (suppl; abstr 8009). L. Sequist, J. Soria, S. Gadgeel, H. Wakelee, R. Camidge, A. Varga, et al., First-in-human evaluation of CO-1686, an irreversible, highly selective tyrosine kinase inhibitor of mutations of EGFR (activating and T790M), J. Clin. Oncol. 32 (2014) 5s (suppl; abstr 8010). NCCN guidelines for management of NSCLC. Version 4, 2014. R. Wang, Y. Pan, C. Li, H. Zhang, D. Garfield, Y. Li, T. Ye, H. Hu, X. Luo, H. Li, Y. Zhang, J. Zhang, X. Zhou, L. Shen, W. Pao, Y. Sun, H. Chen, Analysis of major known driver mutations and prognosis in resected adenosquamous lung carcinomas, J. Thorac. Oncol. 9 (2014) 760–768. Z. Song, B. Lin, L. Shao, Y. Zhang, Therapeutic efficacy of gefitinib and erlotinib in patients with advanced lung adenosquamous carcinoma, J. Chin. Med. Assoc. 76 (9) (2013) 481–485, http://dx.doi.org/10.1016/j.jcma.2013.05.007 Epub 2013; Jun 13.