case report

154    Is distinct EGFR mutation status proof of second simultaneous primary non-small cell lung cancer? 1 3

Abstract  We  present  the  case  of  a  54-year-old  woman diagnosed  with  two  simultaneous  adenocarcinomas  in the  right  and  left  upper  lobe  of  the  lungs.  The  patient was  treated  with  two  curative  intended  resections  and chemotherapy.  The  molecular  analysis  showed  distinct EGFR mutation pattern in both adenocarcinomas of the lung.  During  the  clinical  course,  the  adenocarcinoma without  EGFR  mutation  relapsed  multiple  times  in  the right  lung  resulting  finally  in  pneumonectomy  in  2009. Since then, the patient had no indication of relapse. The case  demonstrates  the  difficulty  to  clinically  discrimi-nate  a  palliative  metastatic  situation  from  a  potential curable  situation  with  two  simultaneous  primary  ad-enocarcinomas of  the  lung. We propose that a different molecular pattern between lesions could be used as an argument for the presence of two simultaneous primary tumors.  In  the  case  of  distinct  EGFR  mutation  pattern, therapy could be performed with curative intent.

Keywords:  Non-small  cell  lung  cancer,  Adenocarcino-ma, EGFR mutation, Simultaneous primary tumor

Case report

In 2005, a 54 years old female patient presented in a very good performance status (ECOG 0) because of repeating 

minor  hemoptoe.  She  had  a  smoking  history  of  5  pack years  but  had  stopped  smoking  25  years  ago.  The  CT scan  showed  a  lesion  in  the  right  lower  lobe  (RLL)  and a second one in the left upper lobe (LUL). Bronchoscopy revealed obstruction of the posterobasal right lower lobe. Histology indicated inflammation, necrosis, and atypical cells suspicious for adenocarcinoma. PET/CT showed a highly  metabolic  active  main  lesion  (5  cm)  in  the  right lower lobe with surrounding smaller metabolic inactive nodes in the same lobe (Fig. 1a). The other lesion (1.2 cm) in the left upper lobe was metabolically inactive (Fig. 1d). No  metabolically  active  mediastinal  lymph  nodes  were present. With the left lesion and the lymph nodes being inactive, the initial clinical stage was cT3 cN0 cM0 (Stage IIB, 7th TNM edition).

A curative intended resection of the RLL with system-atic lymph node resection was performed in September 2005. Histology confirmed an invasive adenocarcinoma with mucinous lepidic (former mucinous bronchioloal-veolar carcinoma, mBAC) predominant growth (Fig. 1b). Minor  papillary  and  acinar-invasive  moieties  were  also present.  The  definitive  stage  was  pT3  pN0  cM0  grade  2 (Stage IIB). In November 2005, a follow-up CT scan indi-cated minimal growth of the lesion in the left upper lobe. Since the CT still showed no pathological lymph nodes, the  small  left  sided  lesion  was  judged  to  be  a  simulta-neous primary carcinoma and a thoracoscopic LUL resec-tion was performed. In its histology, a well-differentiated adenocarcinoma  of  bronchioloalveolar  nonmucinous growth  (nmBAC)  was  diagnosed  (Fig.  1e),  yielding  a pT1 pN0 grade 1 (Stage IA, 7th TNM edition). However, according to the new consensus [1], this lesion needs to be downstaged now to adenocarcinoma-in-situ (AIS) of lepidic nonmucinous growth since no microinvasion was present and the lumens formed by the neoplastic hobnail cells still contained alveolar macrophages (Fig. 1f ). The-refore, the new stage was pTis pN0 cM0 (Stage 0).

The patient received four cycles of chemotherapy with Cisplatin  and  Gemcitabine.  Ten  months  later,  multiple new pulmonary lesions were diagnosed in the right lung, particularly  in  the  upper  lobe.  Treatment  was  started with  Erlotinib  and  Bevacizumab  (clinical  trial  protocol; 

memo (2012) 5:154–156DOI 10.1007/s12254-012-0026-z

Is distinct EGFR mutation status proof of second simultaneous primary non-small cell lung cancer?Ulf Petrausch, Verena Tischler, Walter Weder, Rolf Stahel, Alex Soltermann

U. Petrausch () · R. StahelDepartment of Internal Medicine, Division of Oncology, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerlande-mail: ulf.petrausch@usz.ch

U. PetrauschDivision of Immunology, University Hospital Zurich,  8091 Zurich, Switzerland

V. Tischler · A. SoltermannInstitute for Pathology, University Hospital Zurich,  8091 Zurich, Switzerland

W. WederDivision of Thoracic Surgery, University Hospital Zurich,  8091 Zurich, Switzerland

Received: 21 February 2012 / Accepted: 22 May 2012 / Published online: 16 June 2012© Springer-Verlag Wien 2012

case report

Is distinct EGFR mutation status proof of second simultaneous primary non-small cell lung cancer?    1551 3

inclusion  possible  regardless  of  EGFR  status  [2])  for  20 weeks  with  a  stable  disease.  Due  to  toxicity  (transient ischemic attack), Bevacizumab was stopped but Erlotinib was continued for 9 weeks. With the occurrence of pro-gressive  disease,  Bevacizumab  was  reinstalled  together with  Paraplatin  and  Pemetrexed  in  June  2007.  Twenty four weeks with eight cycles of therapy resulted in stable disease and no severe side effects were observed. Right-sided pulmonary metastases were further treated with a laser resection on patient’s demand. After further disease progression, right sided pneumectomy was performed in March 2009. In this 2009 histology, transition from papil-lary  to  micropapillary  growth  was  observed,  therefore qualifying for grade 3 (Fig. 1c). The last follow-up CT was in June 2011 with no indication of disease.

The  sequence  analysis  of  the  lesion  in  the  RLL  sho-wed no EGFR mutation in exons 18–21. Further, no KRAS mutation (exon 2 and 3) or ALK translocation was found. In contrast, the AIS of the LUL carried the L858R muta-tion [3–5]. The right-sided metastases in 2009 maintained their EGFR wild type status.

We  conclude  that  based  on  both  histological  growth patterns and EGFR status, two distinct neoplastic proces-ses were present in this patient (Fig. 2, schematic repre-sentation of the clinical course with the description of the histopathological and molecular findings in the various 

lesions at different time points). The invasive adenocar-cinoma in RLL was from the beginning multifocally and demonstrated  a  metastatic,  but  interestingly  side-res-tricted course. The AIS was confined to the LUL and see-mingly cured by surgery. Thus, this case corroborates the concept that an invasive adenocarcinoma of mucinous-lepidic  predominant  type  is  often  EGFR  wild  type  [6]. Both tumors were in limited stage (IIB and 0). Early stage mucinous  lepidic  predominant  adenocarcinoma  needs to be clearly separated from an adenocarcinoma in-situ of  nonmucinous  lepidic  type  which  has  better  progno-sis [7]. This patient was treated from the beginning in a curative intention because the tumors in both lungs have been seen as two separate diseases rather than metasta-sis.  In  more  questionable  cases  with  a  strong  need  for curative  treatment  strategies,  the  molecular  informa-tion  can  help  to  delineate  a  metastatic  situation  from two  simultaneous  primary  lung  cancers  in  still  curable stage.  Thus,  we  propose  that  the  molecular  analysis  of pulmonary carcinomas should be performed not only to analyze  markers  which  predict  response  to  therapy  but to give further information about the origin of the tumor. Two  lesions  with  distinct  mutations  can  be  interpreted as a primary tumor and a metastasis with distinct mole-cular  pattern.  The  molecular  evolution  of  metastasis  is well  known  from  analysis  of  metastatic  breast  cancer [8]. However, this scenario is difficult to prove. Therefore patients otherwise curable with two different pulmonary lesions harboring distinct mutations at  the  time of pre-sentation should be treated with curative intent, because from  a  molecular  point  of  view  the  lesions  can  also  be interpreted  as  simultaneous  primary  lesions.  This  con-cept also holds true for other situation like in head neck squamous cell carcinoma (SCC) with additional pulmo-nary squamous cell lesions in the lung being either meta-stasis  or  simultaneous  primary  lung  cancer  lesions.  As recently described, comparative human papilloma virus (HPV) PCR can be performed in this instance to distingu-ish metastasis from primary lung cancer [9].

Fig. 1 a PET/CT scan of RLL, September 2005. b mucinous lepidic growth pattern (AB-PAS mucin stain, lobectomy RLL September 2005). c Transition from papillary to micro-papillary growth pattern (pneumonectomy 2009). d PET/CT scan of RLL, September 2005. e Adenocarcinoma-in-situ (AIS) of LUL, November 2005, absence of invasion but development of inter-stitial fibrosis. f Higher magnification of same AIS with intralu-minal macrophages

Fig. 2  Schematic representation of the clinical course with the description of the histopathological and molecular findings in the various lesions at different time points

case report

156    Is distinct EGFR mutation status proof of second simultaneous primary non-small cell lung cancer? 1 3

Conflict of interest The  authors  declare  that  there  is  no  actual  or  potential conflict of interest in relation to this article.

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