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Figure4.Autopsy specimen of the largest mass in the right lower lobe of the lung. (A) Hematoxylin and Eosin (H&E) staining of the largest mass in the right lower lobe of the lung showed a transitional zone of well-to-moderately differentiated adenocarcinoma and neuroendocrine morphology. (B) H&E staining of the neuroendocrine tumor portion revealed that the tumor grew in sheets and rosette-like structures and exhibited necrosis. The tumor cells were large and had abundant cytoplasm and prominent nucleoli. The neuroendocrine tumor portion was positive for neural cell adhesion molecule (C) and synaptophysin (D), supporting a diagnosis of large-cell neuroendocrine carcinoma (LCNEC). Both the LCNEC (E) and adenocarcinoma portions (F) of the lesion expressed an EGFR mutation with an exon 19 deletion.
Source publication
We herein report a 58-year-old Japanese woman who survived 14 years after surgery for lung adenocarcinoma harboring an epidermal growth factor receptor (EGFR) exon 19 deletion. She developed recurrence, for which she underwent multimodal therapy, including EGFR-tyrosine kinase inhibitor (TKI) administration. She ultimately died from a rapidly progr...
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Background:
The emergence of secondary drug resistance when treating epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) using EGFR-tyrosine kinase inhibitors (EGFR-TKIs), seriously affects the therapeutic efficacy and survival of patients. Here, we report a case of advanced NSCLC focusing on the application of multi...
Citations
... Park (Park et al. 2017) reported a case of epidermal growth factor receptor gene (EGFR)-mutant stage IV lung adenocarcinoma transforming into immunohistochemically proven SCC with the T790M EGFR mutation, leading to acquired resistance to EGFR inhibitors. Other types of frequent transformation following multimodal therapy have been studied with repeated biopsies in many cases: examples include transformation from adenocarcinoma to SCLC and LCNEC (Moriya et al. 2017). Marcoux (Marcoux et al. 2019) reported the transformation of EGFR-mutant adenocarcinoma to SCLC and other neuroendocrine carcinomas after one or more EGFR tyrosine kinase inhibitors had been given. ...
Background:
Histopathological transformation between different types of lung cancer cells has been reported following a variety of anti-tumor treatments. Examples include transformation from lung adenocarcinoma to squamous-cell carcinoma (SCC) and transformation from non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC).
Case report:
A patient with intermittent hemoptysis for 2 days underwent a computed tomography (CT) scan that revealed interstitial pneumonia in addition to two enlarged paratracheal lymph nodes: one on the right (4R) and one on the left (4L) measuring 10 and 7 mm in diameter, respectively (Fig. 1). There was no evidence of a lung or bronchial mass. Bronchoscopy identified an endoluminal primary mass in a superior segmental bronchus of the left lower lobe and pathological examination following surgery confirmed it to be SCC. At 15 months post operation, a CT scan detected that the 4R lymph node had increased in size from 10 to 16 mm in diameter. At the next follow-up 7 months later, a CT scan showed that the R4 lymph node had further increased in size from 16 to 40 mm in the short axis, making it difficult for a surgeon to resect it "en bloc" immediately. The maximum standardized uptake value was 7.5 on PET-CT images. One month following completion of one cycle of neoadjuvant chemotherapy with gemcitabine and nedaplatin, a further CT scan indicated that the lymph node had decreased in size from 40 to 30 mm in the short axis. A complete mediastinal lymphadenectomy via open thoracotomy was performed and the lymph node was resected. Histological examination identified a main large cell neuroendocrine carcinoma (LCNEC) component with a small fraction of small cell carcinoma, confirmed by immunohistochemical analysis and genetic evidence.
Conclusion:
Histopathological transformation from SCC to LCNEC with a small fraction of SCLC may have occurred spontaneously without any treatment.
... 19,20 The transformation of ADC to SCLC or LCNEC has been reported in the development of acquired resistance to EGFR-TKIs. [21][22][23][24][25] Previous gene expression profiling studies of lung ADCs have identified a notable subgroup of lung ADCs that exhibit neuroendocrine characteristics and less favorable survival outcomes. 26 How to treat these proneuroendocrine ADCs still remains unclear. ...
High‐grade neuroendocrine tumors (NETs) of the lung consist of small‐cell lung cancer (SCLC) and large‐cell neuroendocrine carcinoma (LCNEC). Both exhibit aggressive malignancy with poor prognosis. The transformation of lung adenocarcinoma (ADC) to SCLC or LCNEC also contributes to acquired resistance to epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (TKIs). Despite initially being responsive to chemotherapy, high‐grade NET patients inevitably develop drug resistance; thus, novel therapeutic targets are urgently needed for these patients. Our study reported that VGF (nerve growth factor inducible), a factor mainly expressed in neurons during neural development, is highly expressed in SCLC and LCNEC as well as in a subset of ADCs, whereas targeting VGF attenuates cancer cell growth and tumor formation. High VGF expression was associated with advanced stage SCLC and predicted poor prognosis in lung ADC. In addition, EGFR‐TKI selection enriched VGF expression in TKI‐resistant ADC under epigenetic control. The VGF locus possessed the HDAC1 binding site, and treatment of ADC cells with the HDAC1 inhibitor induced VGF expression. High VGF expression was associated with chemoresistance, and silencing VGF induced BMF and BCL2L11 expression and rendered lung cancer cells sensitive to chemotherapy drugs. These findings suggested the potential of VGF as a prognostic factor and therapeutic target in lung cancers with neuroendocrine feature.
... While the majority of LCNECs develop de novo, more rarely, histological transformation from a distinct subtype of NSCLC has been reported (10)(11)(12). This histological transformation can occur as an acquired resistance mechanism to targeted treatment with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) (13)(14)(15)(16)(17). ...
Background
Anaplastic lymphoma kinase (ALK) rearrangements are known oncogenic drivers in non-small cell lung cancer (NSCLC). Few case reports described the occurrence of such rearrangements in large cell neuroendocrine carcinomas (LCNECs) of the lung without information on clinical responses to ALK tyrosine kinase inhibitors (TKIs) in these cases. Currently, neuroendocrine tumors of the lungs are not screened for ALK rearrangements.
Methods
To illustrate the clinical impact of molecular characterization in LCNECs, we report the disease course in three patients with ALK-rearranged metastatic LCNEC from our clinical routine, as well as their treatment response to ALK TKIs (index cases). To gain insight into the prevalence of ALK rearrangements in neuroendocrine tumors of the lung, we analyzed a retrospective cohort of 436 tumor biopsies including LCNEC (n = 61), small cell lung cancer (SCLC) (n = 206), typical (n = 91) and atypical (n = 69) carcinoids, and mixed histology (n = 9) for the presence of ALK rearrangements using a sequential diagnostic algorithm. ALK immunohistochemistry (IHC) was evaluable in 362 cases; fluorescence in situ hybridization (FISH) was evaluable in 28 out of the 35 IHC-positive cases, followed by next-generation sequencing (NGS) that was available in 12 cases.
Results
Within the retrospective cohort, ALK IHC was positive in 35 out of 362 (9.7%) evaluable samples. FISH was positive in 3 out of the 28 (10.7%) evaluable cases: 2 with atypical carcinoids and 1 with LCNEC. Additionally, the 3 index cases showed positive ALK IHC, which was confirmed by NGS. Within the retrospective cohort, NGS confirmed the presence of an ALK genomic rearrangement in one FISH-positive atypical carcinoid where material was sufficient for sequencing. Two out of three patients with metastatic ALK-rearranged LCNEC received up-front treatment with the ALK TKI alectinib and showed rapid tumor response at all metastatic sites, including multiple brain metastases.
Conclusions
ALK rearrangements represent rare but targetable oncogenic driver alterations in LCNEC. Contrarily to NSCLC, the detection of ALK rearrangements in neuroendocrine tumors of the lung is challenging, since ALK IHC can lead to false-positive results and therefore needs confirmation by FISH or NGS. Up-front comprehensive molecular profiling with NGS should be performed in metastatic LCNEC in order not to miss actionable genomic alterations.
... Although most acquired resistance develops due to mutations in the EGFR receptor, activation of bypass intracellular signal pathways, or nongenetic adaptive changes, histologic transformation has been increasingly recognized as a crucial resistance mechanism [7,10]. In addition to the phenotypic transformation to small cell lung carcinoma (SCLC) [11,12], multiple recent reports have described transformations to rare histologic phenotypes, such as large cell neuroendocrine carcinomas (LCNECs) and squamous cell carcinomas (SCCs) (Figure 1) [13,14]. ...
... Although most acquired resistance develops du mutations in the EGFR receptor, activation of bypass intracellular signal pathway nongenetic adaptive changes, histologic transformation has been increasingly recogn as a crucial resistance mechanism [7,10]. In addition to the phenotypic transformatio small cell lung carcinoma (SCLC) [11,12], multiple recent reports have described tran mations to rare histologic phenotypes, such as large cell neuroendocrine carcino (LCNECs) and squamous cell carcinomas (SCCs) (Figure 1) [13,14]. In this article, we try to summarize the mechanisms of histologic transformatio EGFR-mutant NSCLCs and discuss potential therapeutic approaches to conquer thi portant resistance mechanism. ...
... Although LCNECs share many morphologic, phenotypic, and genetic features of SCLC, they also differ in many important ways [62,63]. Only a handful of LCNEC transformations have been reported in EGFR-mutant NSCLCs, thereby limiting our understanding of the mechanisms of this phenotypic change [13,64,65]. Case reports have suggested that in some cases, subclonal cell populations harboring molecular markers of neuroendocrine differentiation such as TP53 and RB1 loss could be present at baseline, which may be selected under the EGFR TKI treatment pressure leading to pathologically evident transformation in due course [64]. ...
With the advent of potent EGFR tyrosine kinase inhibitors (TKIs), the treatment landscape of EGFR-mutant lung adenocarcinomas has changed drastically in recent years. However, the development of resistance to EGFR TKIs remains a critical barrier to improving survival in these patients. Histologic transformations to small cell lung carcinoma, large cell neuroendocrine carcinoma, squamous cell carcinoma, and the sarcomatoid phenotype have been increasingly recognized as important mechanisms of resistance. In this article, we summarize the known biological bases for such phenotypic switches in regard to EGFR TKIs and describe novel pathways that might be harnessed to develop effective novel therapies for patients with EGFR-mutant non-small cell lung cancers.
... It has been seen in other malignancies, theorised to be a result of acquired mutations to certain chemotherapeutic agents. 5 In our particular case, the patient had not had any exposure to chemotherapy and thus demonstrates a de novo metastatic transformation. ...
Metastatic urothelial carcinoma of the bladder is generally considered to be an aggressive disease with many recognised variants, however what is unique about our patient is the metastatic transformation from a urothelial primary malignancy with sarcomatoid variation to a neuroendocrine deposit within the liver. From what we have identified, this pattern of pathological transformation has not been reported for a urothelial malignancy in the literature. We present a 64 year old male whom we believe is the first reported case of a primary urothelial malignancy presenting de-novo with metastatic liver deposits showing neuro-endocrine transformation.
... For example, two patients with primary lung ADC show SCC or SCLC in brain metastasis whereas another patient with primary lung SCC shows ADC in brain metastasis. Transitions from ADC to LCNEC, or Ad-SCC to SCLC have also been reported [63,64]. Obviously, our understanding of pathological transition is still very limited. ...
Despite the tremendous efforts for improving therapeutics of lung cancer patients, its prognosis remains disappointing. This can be largely attributed to the lack of comprehensive understanding of drug resistance leading to insufficient development of effective therapeutics in clinic. Based on the current progresses of lung cancer research, we classify drug resistance mechanisms into three different levels: molecular, cellular and pathological level. All these three levels have significantly contributed to the acquisition and evolution of drug resistance in clinic. Our understanding on drug resistance mechanisms has begun to change the way of clinical practice and improve patient prognosis. In this review, we focus on discussing the pathological changes linking to drug resistance as this has been largely overlooked in the past decades.
... Remarkably, treatment with TKIs has shown efficacy in LCNEC harboring EGFR activating mutations [40][41][42]. As reported in Table 3, rare cases have reported the transition from ADC to LCNEC as a morphologic changes associated with resistance to TKI therapy [43][44][45][46]. The same EGFR mutation identified in the original ADC is retained by the malignant neuroendocrine cells [44]. ...
... The same EGFR mutation identified in the original ADC is retained by the malignant neuroendocrine cells [44]. In an autoptical case, Moriya et al. [45] again by "molecular autopsy" showed that among different lung neoplastic nodules, an area featured LCNEC changes with cells showing the activating EGFR mutation. Interestingly, Kogo et al. [46] showed in the transition area from ADC to LCNEC a very strong expression of Rb, which is a typical example of aggressive neuroendocrine neoplasm. ...
In the late stages of non-small cell lung cancer, the detection of sensitizing mutations of the epidermal growth factor receptor (EGFR) is mandatory to select patients' treatment with first- or second-generation tyrosine kinase inhibitors (TKIs). In patients showing progressive disease, the assessment of the EGFR exon 20 resistance point mutation p.T790M is required for third-generation TKI administration. However, molecular analysis does not capture all the different mechanisms of resistance against these molecules. A variety of morphological changes associated with acquired resistance have also been described. Since an altered morphology may be the only clue to acquired resistance, cytopathology still plays a relevant role in this setting. In this comprehensive review, we have focused on the relevance of squamous cell carcinoma, small cell lung cancer and large-cell neuroendocrine carcinoma transitions from adenocarcinoma resistant to TKIs.
Objective
Treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs)can occasionally lead to interstitial lung disease (ILD), and the appropriate treatment after recovery from ILD remains controversial. AC0010 is an investigational third-generation TKI used in China to selectively target the T790M mutation. Here, we describe a patient who developed ILD after AC0010 treatment and was then successfully re-challenged with osimertinib.
Methods
The patient was a 67-year-old male with a diagnosis of metastatic pulmonary adenocarcinoma with an L858R mutation on exon 21. Acquired T790M mutation was confirmed by re-biopsy after progression on erlotinib treatment. The patient was treated with AC0010, and developed ILD 54 days after treatment initiation. Following his recovery from ILD, osimertinib (80 mg/day) was administered with no adverse effects. After progression on osimertini\b 11 months later, a histological transformation from adenocarcinoma to large-cell neuroendocrine carcinoma was confirmed by re-biopsy, with a marked increase in serum neuron-specific enolase.
Conclusions
This is the first report of interstitial pneumonitis caused by AC0010. Osimertinib re-challenge after recovery from ILD was a safe and effective treatment option. Our report further highlights that pathological transformation of large-cell neuroendocrine carcinoma represents one of the resistance mechanisms of osimertinib, and may be accompanied by an increase in serum neuron-specific enolase.
Histologic transformation from adenocarcinoma to squamous cell carcinoma in lung cancer has not been reported as a mechanism of resistance to ALK inhibition. This report describes the clinical course of a female former light smoker with metastatic lung adenocarcinoma whose tumor underwent histologic transformation from a well-differentiated lung adenocarcinoma to a well-differentiated lung squamous cell carcinoma in the same location at the left mainstem bronchus while maintaining the ALK fusion oncogene without any resistance mutations. After experiencing disease progression while on crizotinib, the patient participated in clinical trials that provided early access to the novel ALK inhibitors ceritinib and alectinib before they were commercially available. Tumor recurrence occurred at the primary and metastatic central nervous system sites (ie, brain and spine). At tumor progression, liquid biopsy and tumor genomic profiling of plasma cell-free DNA next-generation sequencing (NGS) provided an accurate diagnosis with a short turnaround time compared with the tissue-based targeted capture NGS. The patient received several courses of radiation primarily to the brain and spine during her disease course. Her disease did not respond to the immune checkpoint inhibitor nivolumab, and she died on home hospice approximately 4 years after diagnosis. This case supports the importance of both histopathologic assessment and comprehensive genomic profiling in selecting appropriate treatment for patients with refractory, metastatic, ALK oncogene–driven non–small cell lung cancer. Use of symptom-directed radiation in tandem with ALK inhibitors contributed to the disease and symptomatic control and prolonged survival in this patient.
