| Background:NUT carcinoma was newly listed in version 2015 of WHO,and NUT carcinoma and Primary pulmonary lymphoepithelioma-like carcinoma(PPLELC)were singled out as unclassified groups.These two kinds of tumors are very unique,their pathogenesis,epidemiology,clinical manifestations,histological morphology,diagnostic methods,treatment options and prognosis are different.However,some morphology and immunophenotype of these two tumors overlap with squamous cell carcinoma,which may have been misdiagnosed as squamous cell carcinoma of the lung in the past.We reviewed the past cases of lung squamous cell carcinoma and rediagnosed these two types of tumors by tissue microarray technique(TMA),from the aspects of clinical features,pathological morphology,immunohistochemistry,molecular pathology,genomics and so on.In order to improve the level of awareness and diagnosis of it.Method:a retrospective analysis of surgically resected lungs 918cases in the Cancer Hospital of the Chinese Academy of Medical Sciences and Peking Union Medical College from January 1,2014 to April 24,2017.Tissue microarray technique(TMA),was used for immunohistochemical staining of NUT,CD99,CD56,CD34,GPC3,MLH1,MSH2,MSH6,PMS2 and EBER in situ hybridization.Lung NUT carcinoma was further studied by fluorescence in situ hybridization(FISH)and NGS to detect the genomic changes of the whole exon of NUT carcinoma.the clinical,pathological,genomic and follow-up results of NUT carcinoma and PPLELC were summarized.Results:(1)There were 822 males(89.54%)and 96 females(10.45%)in this group.The ratio of male to female was 8.56:1,the median age was 67 years old,the range was 33?84 years old,mainly the elderly,618 cases(67.32%)were older than 60 years old.The tumors were mainly central type,involving segmental bronchus in 686 cases(74.73%)and pleura in 267 cases(29.08%).According to the eighth edition of AJCC,and there were 263 cases(28.65%)with stage T2 tumors.Hilar and peripheral lymph nodes were involved in 372 cases(40.52%).The differentiation of basal squamous cell carcinoma was found in 300 cases(32.68%)and 155 cases(155/300,51.67%)with a proportion of more than 50%.713 cases(77.67%)showed at least 30%of the areas with more intensive inflammatory cell infiltration,a wide range of inflammatory cell infiltration(>60%),more dense(>80/HPF)in 67 cases(9.4%).(2)There were 2 cases(0.22%)nucleus positive with NUT protein and 13 cases(1.41%)with different degrees of cytoplasmic positive with NUT protein in 918 cases of poorly differentiated squamous cell carcinoma.The positive rates of CD99,CD56,CD34 and GPC3 in poorly differentiated squamous cell carcinoma were 47 cases(5.12%),31 cases(3.38%),8 cases(0.87%)and 150 cases(16.34%),respectively.Mismatch repair protein(MMR)deletion was found in 13 cases(1.42%),MLH1/PMS2 deletion in 8 cases(0.87%),PMS2 deletion in 3 cases(0.33%)and MSH6 deletion in 2 cases(0.22%).EBER in situ hybridization was positive in 3 cases(0.33%).(3)FISH confirmed that NUT gene was splited in 2 cases nucleus positive with NUT by immunohistochemistry,but no NUT gene was splited in 13 cases with cytoplasm positive of NUT.(4)Two patients with NUT Carcinoma(0.22%)were 44 years old male,stage III B and IV A at the time of operation,and died 9 months and 6 months after operation.Histologically,the cells were small to medium sized round cells,and sudden keratosis could be seen in case 1.(5)The results of total exon sequencing with NGS in NUT carcinoma showed that TMB was found in 2.63 mutation/MB and 7.2 mutation/MB;the fusion of NUT-NSD3 and NUT-BRD3,respectively.The sequencing results were compared with the genomics of lung squamous cell carcinoma published by TCGA in 2012,which screened the 10 genes that changed the most.With the exception of case 2,which has a mutation in MLL2(KMT2D),it is inconsistent.(6)There were 3 cases of PPLELC(0.32%),including 43-year-old male,38-year-old male and 44-year-old female.at the time of operation,stage IIIA,IA3 and IA2 were performed.All the patients were followed up for 31?36 months and all of them were alive.Among 67 cases of lymphoid interstitial lung cancer,3 cases(4.48%)were EBV+,9cases(13.43%)were dMMR,and 55 cases(82.09%)were negative for EBV and dMMR.Conclusions:Lung NUT carcinoma and PPLELC are two unique tumors.their pathogenesis,epidemiology,clinical manifestations,histological morphology,diagnostic methods,treatment options and prognosis are different.Immunohistochemical and molecular pathological methods are needed to identify them from squamous cell carcinoma of the lung for more accurate treatment.Objective Immunohistochemistry and/or mucin staining was used for histological subtype of poorly differentiated solid lung cancer with molecular testing of epidermal growth factor receptor(EGFR)mutation and anaplastic lymphoma kinase(ALK)gene rearrangement.Methods 827 cases of non-small cell lung cancer at Beijing Hospital in the past 3 years were reviewed,167 cases of solid poorly differentiated lung cancer were identified,and further divided by mucin staining(D-PAS)and IHC with a group of 10 antibodies(CK7,vimentin,Ki-67,CK5/6,p40,TTF1,Napsin,A,CD56,chromogranin A,synaptophysin).Paraffin embedded specimens were subjected to mutation analysis of exons 18,19,20 and 21 of the EGFR gene by amplification refractory mutation system(ARMS)method.IHC(Ventana D5F3)for ALK gene rearrangement were carried out,and fluorescence in situ hybridization(FISH)was used to verify.Results There were 79 females and 88 males.The patient's age ranged from 35 to 77 years(mean 62 years).The cases which arranged in a poorly solid pattern(at least>10%),be short of typical histological arrangement of adenocarcinoma,squamous cell carcinoma,neuroendocrine carcinoma were select to further divided into 64 cases(38.32%)adenocarcinoma,34 cases(20.35%)squamous cell carcinoma,21 cases(12.57%)large cell neuroendocrine carcinoma,5 cases(2.99%)combined large cell neuroendocrine carcinoma,2 cases(1.20%)adenosquamous carcinoma and 41 cases(24.56%)large cell carcinoma by mucin staining(D-PAS)and IHC.The Ki-67 positive rate was about 5%?65%.Mutations of EGFR were detected in 5 cases(7.81%)of adenocarcinoma(19del 3 cases,L858R 2 cases);2 cases(3.12%)of ALK-rearranged samples were identified by immunohistochemistry(Ventana D5F3)and FISH was used to verify it.Conclusions Poorly differentiated solid lung cancer lacks morphological differentiation features can be further divided into histological subtypes by mucin staining(D-PAS)and immunohistochemistry.Molecular testing also can be done to find the molecular target to provide patients with more accurate treatment,in order to improve the prognosis.Objective The diagnostic criteria of lung biopsy specimens with 2015 WHO lung tumor classification were used to investigate the pathological diagnosis of lung biopsy specimens and detection the changes of major tumor driving genes such as epidermal growth factor receptor(EGFR).Methods The clinical data,pathological sections,immunohistochemical sections and special staining sections of 806 cases lung biopsy specimens from Beijing Hospital in the past 3 years(from July 2015 to July 2018)were retrospectively analyzed.483 cases of lung cancer were reclassified using the 2015 WHO lung tumor classification and the results of related gene mutation were summarized and analyzed.Results In the past three years,the number of lung cancer was 58 cases,166 cases and 259 cases in turn,totally 483 cases.221 were female and 262 were male,aged 37 to 85 years old,with a median age of 65 years old.Including 40 cases small cell carcinoma(8.28%),11 cases large cell neuroendocrine carcinoma(2.28%),3 cases combined neuroendocrine carcinoma(0.62%),2 cases atypical carcinoid(0.41%),208 cases adenocarcinoma(43.06%),92 cases non-small cell carcinoma,favor adenocarcinoma(19.05%),66 cases squamous cell carcinoma(13.66%),42 cases non-small cell carcinoma,favor squamous cell carcinoma(8.70%),16 cases non-small cell carcinoma,not otherwise specified(3.31%),3 cases(0.62%)non-small cell carcinoma,possible adenosquamous carcinoma.107 cases(52.97%)of EGFR mutations were observed in 202 cases.86 cases(64.66%)had EGFR mutation in 133 cases of adenocarcinoma,18 cases(34.62%)had EGFR mutation in 52 cases of non-small cell carcinoma,favor adenocarcinoma.22 cases with T790M mutation was detected in 27 patients with EGFR after TKI targeted drug therapy.Immunohistochemical Ventana ALK(D5F3)was positive in 3 of 354 cases of non-small cell lung cancer.It was confirmed by EML4-ALK fusion gene fluorescence PCR.ROS1 gene fusion was found in 1 out of 38 cases.Detection of splicing mutations in exon 14 of MET gene in a case of non-small cell carcinoma with spindle cell carcinoma differentiation.Conclusions The new diagnostic criteria for small lung biopsy specimens of the 2015 WHO lung tumor classification can better diagnose lung biopsy specimens in order to guide the treatment more accurately and improve the prognosis. |
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