Combined Small Cell Carcinoma Research Articles

Molecular subtypes, predictive markers and prognosis in small-cell lung carcinoma

AimsA new molecular subtype classification was proposed for small-cell lung carcinoma (SCLC). We aimed to further validate the classification in various SCLC patient samples using immunohistochemistry (IHC) to highlight its...

Molecular subtype expression and genomic profiling differ between surgically resected pure and combined small cell lung carcinoma

A new molecular subtype classification method has been proposed for small cell lung carcinoma (SCLC). However, little is known about the differences between the pure (P-SCLC) and combined subtypes (C-SCLC). We aimed to compare the molecular subtype expression and genomic profiling in terms of clinical relevance between the two groups. 154 surgically resected SCLCs were analyzed for protein expression of four subtypes (ASCL1, NEUROD1, POU2F3, and YAP1) and two predictive markers (DLL3 and MYC) by immunohistochemistry (IHC). We also performed whole exome sequencing of 60 samples to examine genomic profiles. A total of 113 patients with P-SCLC and 41 with C-SCLC were included. In P-SCLC and C-SCLC, the expression of these markers was 78.8% and 41.5%, 98.2% and 97.6%, 42.5% and 51.2%, 38.9% and 85.4%, 85.0% and 68.3%, and 24.8% and 34.1%, respectively. ASCL1 and DLL3 were highly expressed in P-SCLC (p=0.000 and p=0.021, respectively), and YAP1 expression was significantly enriched in C-SCLC (p=0.000). NGS results, including 45P-SCLCs and 15C-SCLCs, indicated that EGFR gene mutations were mostly observed in C-SCLCs (p=0.000). C-SCLC showed higher CNA burden and wGII than P-SCLC (p<0.01 and p<0.05); conversely, P-SCLC had higher TMB burden and SDI (p<0.05 and p<0.05). YAP1 expression was associated with poor prognosis in P-SCLC but with favorable prognosis in C-SCLC. P-SCLC and C-SCLC are heterogeneous diseases characterized by different molecular subtype expressions and genomic profiles. Our data provide a basis for adopting histological subtype-based treatments, and further prospective studies are required to confirm our conclusions.

Clinicopathological and Treatment Patterns of Combined Small-Cell Lung Carcinoma with Future Insight to Treatment: A Population-Based Study.

Primary lung cancer is the most common cause of cancer-related mortality in the United States (US). Approximately 90% of lung cancers are associated with smoking and the use of other tobacco products. Based on histology, lung cancers are divided into small-cell lung carcinomas (SCLCs) and non-small-cell lung carcinomas (NSCLCs). Most SCLCs are of the pure subtype, while the rare combined SCLCs contain elements of both small-cell and non-small-cell morphologies. This study sought to evaluate the demographics, clinical factors, molecular abnormalities, treatment approaches, and survival outcomes with combined SCLC and NSCLCs. Data on 2126 combined SCLC patients was extracted from the Surveillance Epidemiology and End Result (SEER) database from 2000 to 2018. Data extracted for analyses included age, sex, race, tumor size, tumor location, metastasis status, stage at diagnosis, treatment received, and treatment outcomes. Multivariate analysis was performed using Statistical Product and Service Solutions (SPSS) software. The patients had a median age of 68 years; 43.9% of the patients were female and 56.1% were male; 84.5% were White and 11.7% were African Americans. The majority of patients had a poorly differentiated disease at 29.6%; 17% were undifferentiated, 3.2% were moderately differentiated, and 0.8% were well differentiated. Chemotherapy was the most common treatment modality (45.3%); 17% underwent surgery only, 10.3% underwent surgery followed by adjuvant chemotherapy, and 10% underwent radiation after surgery. Five-year cancer-specific survival was 15.2% with surgery alone, and combined surgery and chemotherapy provided the highest percentages (38.3% and 34.7%, respectively). Females had significantly higher 1- and 5-year cancer-specific survival rates compared to males (59.3% and 29.9% vs. 48.0% and 23.7, respectively; p < 0.001). Well-differentiated tumors had significantly higher survival compared to other gradings (p < 0.001). Survival decreased as tumor staging moved distally from localized to regional to distant (p < 0.001). Metastasis to bone, liver, brain, and lung significantly decreased survival in comparison to patients who did not have any metastasis (p < 0.001). Females had significantly shorter survival compared to their counterparts when metastasis was to the bone, brain, or liver (p < 0.001). Multivariate analysis identified male sex (Hazard Ratio (HR) = 1.2), undifferentiated grade (HR = 1.9), regional extent of disease (HR = 1.7), distant extent of disease (HR = 3.7), and metastasis to liver (HR = 3.5) as variables associated with worse survival. Combined SCLC is overall very rare. However, the frequency of presentation with combined SCLC is on the rise, in part due to improvements in diagnostic techniques. Despite advances in therapies, treating combined SCLC is challenging, and novel therapies are not utilized, owing to low rates of targetable mutations. Combined SCLC has higher survival rates if well differentiated.

Comprehensive genetic analysis of histological components of combined small cell carcinoma.

BackgroundCombined small‐cell lung cancer (cSCLC) is a rare type of small‐cell lung cancer (SCLC) that includes both SCLC and non‐small‐cell lung cancer (NSCLC). The molecular biological mechanisms underlying the heterogeneity of histological types in combined or metachronously transformed SCLC (mtSCLC) remain unclear. This study aimed to investigate the relationship between genetic alterations and each histological component heterogeneously detected in cSCLC and mtSCLC.MethodsThis study included four cSCLC cases and one mtSCLC case. Formalin‐fixed and paraffin‐embedded sections of each histological component of these tumors were subjected to next‐generation sequencing (NGS) and quantitative reverse transcription‐polymerase chain reaction to investigate the genetic mutations and expression levels of neuroendocrine cell‐specific transcription factors (achaete‐scute homolog‐1 [ASCL1], brain‐2 [BRN2] also known as POU domain class 3 transcription factor 2, nuclear factor 1 B [NF1B], insulinoma‐associated protein 1 [INSM1], and thyroid transcription factor‐1 [TTF‐1]).ResultsNGS analysis revealed that SCLC and NSCLC components share the same somatic mutations detected most frequently in TP53, and also in RB1 and EGFR. Gene expression analysis showed ASCL1 expression was significantly lower in the NSCLC component than in the SCLC component.ConclusionWe conclude that the morphological evolution of heterogeneous histological components in cSCLC may be associated with differences in ASCL1 expression levels, but not in acquired somatic gene mutations.

Autopsy case of a patient with rapidly progressive combined small‐cell lung carcinoma with spindle‐shaped cell tumor

A 69‐year‐old Japanese man visited our hospital because of worsening shortness of breath. His chest computed tomography (CT) showed a giant left lung mass with a massive left pleural effusion. He could not be treated with chemotherapy and eventually died from a rapidly progressive tumor. He was diagnosed with combined small cell lung carcinoma (C‐SCLC) with spindle‐shaped cell tumor at autopsy. C‐SCLC is characterized by pathologically concurrent SCLC and adenocarcinoma or squamous cell carcinoma, or rarely, spindle‐shaped cell tumor. The clinical course of C‐SCLC with spindle‐shaped cell tumor has not previously been determined. Our patient's tumor increased by 2.59‐fold in 20 days. The combination of C‐SCLC with spindle‐shaped cell tumor suggested rapid progression and a poor prognosis.

Multiple endotracheal metastases of combined small cell lung carcinoma.

Key messageWe report a very rare case of combined small cell lung carcinoma (C‐SCLC) which presented as persistent cough and was due to endotracheal metastases. Clinicians should be aware of this unusual site of metastases from a C‐SCLC.

Combined SCLC clinical and pathological aspects.

Combined small cell lung carcinoma (C-SCLC) is rare and accounts for 1-3% of all lung cancer cases. Although its incidence has increased recently, there are limited studies on it. The records of patients admitted to our hospital between January 2015 and December 2019 and diagnosed with histologically proven combined small cell were scanned retrospectively and reviewed. 31 patients were analyzed. The average follow-up time was 10 months. The radiotherapy (RT) rate, surgery rate, and large cell malignancy rate were significantly lower in the ex group than in the living group (p=0.024, p=0.023, p=0.015). The rates of extensive disease, metastasis, and thyroid transcription factor 1 (TTF1) were significantly higher in the old group than in the living group (p=0.000, p=0.000, p=0.029, respectively). In the univariate model, sequential RT, fatigue, lactate dehydrogenase (LDH), stage, metastasis, contralateral lung metastasis, chemotherapy were observed to be significantly effective in predicting survival time (p=0.000, p=0.050, p=0.011, p=0.004, p=0.004, p=0.045, p=0.009). In the multivariate model, independent (p=0.015, p=0.022, p=0.049) efficacy of RT, stage, and chemotherapy in predicting survival was observed. C-SCLC is a specific mixed carcinoma and reports evaluating this type are still scarce. The stage of the disease, radiotherapy and chemotherapy are extremely important in predicting survival.

Deep Learning Facilitates Distinguishing Histologic Subtypes of Pulmonary Neuroendocrine Tumors on Digital Whole-Slide Images.

Simple SummaryChallenges persist in diagnosing pulmonary neuroendocrine tumors. Our case study shows that deep learning combined with convolutional neural networks has the potential to assist in the diagnosis of pulmonary neuroendocrine tumors from digital whole-slide images.The histological distinction of lung neuroendocrine carcinoma, including small cell lung carcinoma (SCLC), large cell neuroendocrine carcinoma (LCNEC) and atypical carcinoid (AC), can be challenging in some cases, while bearing prognostic and therapeutic significance. To assist pathologists with the differentiation of histologic subtyping, we applied a deep learning classifier equipped with a convolutional neural network (CNN) to recognize lung neuroendocrine neoplasms. Slides of primary lung SCLC, LCNEC and AC were obtained from the Laboratory of Clinical and Experimental Pathology (University Hospital Nice, France). Three thoracic pathologists blindly established gold standard diagnoses. The HALO-AI module (Indica Labs, UK) trained with 18,752 image tiles extracted from 60 slides (SCLC = 20, LCNEC = 20, AC = 20 cases) was then tested on 90 slides (SCLC = 26, LCNEC = 22, AC = 13 and combined SCLC with LCNEC = 4 cases; NSCLC = 25 cases) by F1-score and accuracy. A HALO-AI correct area distribution (AD) cutoff of 50% or more was required to credit the CNN with the correct diagnosis. The tumor maps were false colored and displayed side by side to original hematoxylin and eosin slides with superimposed pathologist annotations. The trained HALO-AI yielded a mean F1-score of 0.99 (95% CI, 0.939–0.999) on the testing set. Our CNN model, providing further larger validation, has the potential to work side by side with the pathologist to accurately differentiate between the different lung neuroendocrine carcinoma in challenging cases.

A case of combined small cell carcinoma of the lung with carcinosarcoma

A case of combined small cell carcinoma of the lung with carcinosarcoma

Comparative Study of Pulmonary Combined Large-Cell Neuroendocrine Carcinoma and Combined Small-Cell Carcinoma in Surgically Resected High-Grade Neuroendocrine Tumors of the Lung.

ObjectivesPulmonary large-cell neuroendocrine carcinoma (LCNEC) and small-cell lung cancer (SCLC) are both classified as pure and combined subtypes. Due to the low incidence and difficult diagnosis of combined LCNEC (C-LCNEC) and combined SCLC (C-SCLC), few studies have compared their clinical features and prognosis.Materials and MethodsWe compared the clinical features, mutation status of driver genes (EGFR, ALK, ROS1, KRAS, and BRAF), and prognosis between C-LCNEC and C-SCLC. Univariate and multivariate Cox regression analyses were applied for survival analysis.ResultsWe included a total of 116 patients with C-LCNEC and 76 patients with C-SCLC in the present study. There were significant differences in distribution of smoking history, tumor location, pT stage, pN stage, pTNM stage, visceral pleural invasion (VPI), and combined components between C-LCNEC and C-SCLC (P<0.05 for all). C-SCLC was more advanced at diagnosis as compared to C-LCNEC. The incidence of EGFR mutations in C-LCNEC patients was higher than C-SCLC patients (25.7 vs. 5%, P=0.004). We found that tumor size, pN stage, peripheral CEA level, and adjuvant chemotherapy were independently prognostic factors for DFS and OS in C-LCNEC patients, while peripheral NSE level, pT stage, pN stage, VPI and adjuvant chemotherapy were independently associated with DFS and OS for C-SCLC patients (P<0.05 for all). Propensity score matching with adjustment for the confounders confirmed a more favorable DFS (P=0.032) and OS (P=0.019) in patients with C-LCNEC in comparison with C-SCLC patients upon survival analysis.ConclusionsThe mutation landscape of driver genes seemed to act in different way between C-SCLC and C-LCNEC, likely by which result in clinical phenotype difference as well as better outcome in C-LCNEC.

1114P Comparative study of combined large cell neuroendocrine carcinoma and combined small cell carcinoma in resected high-grade neuroendocrine tumors of the lung

Large cell neuroendocrine carcinoma (LCNEC) and small cell carcinoma (SCLC) are both classified as pure and combined subtypes. Due to the low incidence and difficult diagnosis of combined LCNEC (C-LCNEC) and combined SCLC(C-SCLC), no studies have been conducted to compare their clinical features and prognosis.

Anti-GABAB receptor encephalitis associated with combined small cell lung carcinoma

Autoimmune encephalitis with antibodies against the gamma-aminobutyric acid-B receptor is a relatively rare disease. We report a case with characteristic symptoms of limbic encephalitis associated with combined small cell lung carcinoma. The brain magnetic resonance imaging showed bilateral temporal lesions and the photoemission tomography revealed regional heterogenous metabolism across the brain. The double labeling of anti-gamma-aminobutyric acid-B receptor autoantibodies both in the tissues of neuroendocrine and small cell neoplasia was a unique feature of this patient.

Combined small cell lung carcinoma harboring ALK rearrangement: A case report and literature review

Combined small cell lung cancer (c‐SCLC) is a relatively rare subtype of SCLC and is defined by the combination of SCLC and any elements of non‐small cell carcinoma (NSCLC). Standard chemotherapy for patients with c‐SCLC has not yet been established. Gene mutations such as epidermal growth factor receptor (EGFR) mutations may be detected in patients with c‐SCLC. However, little is known about anaplastic lymphoma kinase (ALK) rearrangement in c‐SCLC patients. Here, we report a young female patient who was successfully treated with alectinib for ALK‐positive c‐SCLC after failure of immunochemotherapy for SCLC and cytotoxic chemotherapy for adenocarcinoma. Moreover, we performed a literature review of EGFR‐ or ALK‐positive c‐SCLC patients. Our report suggests that ALK testing may be justified in patients with SCLC that contain an adenocarcinoma component.Key pointsSignificant findings of the study• This is the first report describing the treatment course comprising immunochemotherapy and ALK‐TKI in a patient with c‐SCLC harboring ALK rearrangement.What this study adds• Our case and literature review suggest that although ALK mutation is rare in patients with c‐SCLC, its identification and treatment with ALK‐TKIs may contribute to clinical benefits.

SCLC Subtypes Defined by ASCL1, NEUROD1, POU2F3, and YAP1: A Comprehensive Immunohistochemical and Histopathologic Characterization.

Recent studies have identified subtypes of small cell lung carcinoma (SCLC) defined by the RNA expression of ASCL1, NEUROD1, POU2F3, and YAP1 transcriptional regulators. There are only limited data on the distribution of these markers at the protein level and associated pathologic characteristics in clinical SCLC samples. The expression of ASCL1, NEUROD1, POU2F3, and YAP1 was analyzed by immunohistochemistry in 174 patient samples with SCLC. Subtypes defined by these markers were correlated with histologic characteristics, expression of classic neuroendocrine markers (synaptophysin, chromogranin A, CD56, INSM1), and other SCLC markers, including the neuroendocrine phenotype-associated markers TTF-1 and DLL3. ASCL1 and NEUROD1 expression had the following distribution: (1) 41% ASCL1+/NEUROD1-; (2) 37% ASCL1+/NEUROD1+; (3) 8% ASCL1-/NEUROD1+; and (4) 14% ASCL1-/NEUROD1-. On the basis of their relative expression, 69% of cases were ASCL1-dominant and 17%were NEUROD1-dominant. POU2F3 was expressed in 7% of SCLC and was mutually exclusive of ASCL1 and NEUROD1. YAP1 was expressed at low levels, primarily in combined SCLC, and was not exclusive of other subtypes. Both ASCL1-dominant and NEUROD1-dominant subtypes were associated with neuroendocrine markerhigh/TTF-1high/DLL3high profile, whereas POU2F3 and other ASCL1/NEUROD1 double-negative tumors were neuroendocrine markerlow/TTF-1low/DLL3low. This is the first comprehensive immunohistochemical and histopathologic analysis of novel SCLC subtypes in patient samples. We confirm that ASCL1/NEUROD1 double-negative tumors represent a distinct neuroendocrine-low subtype of SCLC, which is either uniquely associated with POU2F3 or lacks a known dominant regulator. The expression profiles of these markers appear more heterogeneous in native samples than in experimental models, particularly with regard to the high prevalence of ASCL1/NEUROD1 coexpression. These findings may have prognostic and therapeutic implications and warrant further clinical investigation.

Lung nuclear protein in testis carcinoma in an elderly Korean woman: A case report with cytohistological analysis

Nuclear protein in testis (NUT) carcinoma is a rare, aggressive carcinoma that is a diagnostic challenge for pathologists. Here, we report a case of NUT carcinoma in a 63‐year‐old woman with uncommon immunohistochemical results. The initial bronchoscopic biopsy revealed a poorly differentiated carcinoma with p63 immunohistochemical stain positivity. However, the cytomorphological features of the pleural fluid were unusual. Immunohistochemical staining of the pleural fluid revealed diffuse positivity for vimentin and focal positivity for cytokeratin and neuroendocrine markers. Because of chemoresistance, other malignancies, including sarcomatoid carcinoma, combined small cell carcinoma, and an unusual form of NUT carcinoma, were considered as differential diagnoses. The diagnosis of NUT carcinoma was confirmed using NUT‐specific antibodies and fluorescence in situ hybridization. The current case was a diagnostic challenge because of the poorly differentiated cytomorphology and uncommon immunohistochemical results. Pathologists and clinicians should consider NUT carcinoma in the differential diagnosis, as this malignancy has a dismal prognosis and needs to be diagnosed accurately for the most effective treatment.Key points Metastatic NUT carcinoma can show diffuse vimentin positivity and focal neuroendocrine marker positivity. NUT carcinoma can be misdiagnosed as basaloid squamous cell carcinoma in routine diagnosis, especially in older‐aged patients.This study was a diagnostic challenge because of the poorly differentiated cytomorphology and uncommon immunohistochemical results for NUT carcinoma. Pathologists should differentially diagnose NUT carcinoma when rare cytohistological features are observed at any age.

Aetiologic Diagnosis and the Efficacy of Interventional Treatment of Intraluminal Central Airway Spheroid Masses

<i>Objective</i> To explore the diagnosis of, clinical characteristics of and effects of interventional therapy for intraluminal central airway spheroid masses. <i>Methods</i> Forty-four patients with intraluminal central airway spheroid masses were summarized retrospectively, and the clinical characteristics and therapy were analysed. <i>Results</i> Cough and shortness of breath were the predominant symptoms, followed by hemoptysis, fever and chest pain. The aetiologic diagnoses were 12 cases of inflammatory granulomas, 5 cases of foreign matter, 5 cases of squamous carcinoma, 4 cases of leiomyoma, 3 cases of lipomyoma, 2 cases of inflammatory myofibroblastic tumor, and one case each of glomus tumor, adenocarcinoma, mucoepidermoid carcinoma, malignant melanoma metastasis, carcinoid, adenoid cystic carcinoma, chondrosarcoma, combined small cell carcinoma, hamartoma, mixed tumor, neurilemmoma, acidophilic adenoma and salivary gland tumor. The numbers of masses located in the trachea, left main bronchus, right main bronchus and bronchus intermedius were 20, 13, 7, and 4, respectively. Electrocautery snare and electrocoagulation probe was the most commonly used interventional therapy method, followed by argon plasma coagulation and cryotherapy; stent implantation was used in 1 case. Thirty-five cases achieved a complete response or partial response after treatment, 8 cases achieved a mild response, and 1 had no response. <i>Conclusion</i> The symptoms of intraluminal central airway spheroid masses were atypical and easily misdiagnosed or missed; benign lesions were the leading cause, and the first pathological type was inflammatory granuloma. Endoscopic intervention was the effective, safe technique.

Applicability of the PACIFIC trial results in patients not eligible for the PACIFIC trial: Canadian rapid consensus statement and recommendations.

BackgroundThe PACIFIC study established durvalumab as a standard of care for consolidation therapy in patients treated with radical intent chemoradiation for stage III inoperable non-small cell lung cancer. In clinical practice, many patients are not eligible for trials, yet radical intent chemoradiation may still be used. MethodsA virtual anonymous tumour board Delphi-model was used in order to generate consensus on the use of durvalumab in six clinical situations where chemoradiation is used in clinical practice and recommended in guidelines, yet not PACIFIC eligible. Two anonymous iterations were sent and recommendations were circulated for approval and comment. Results are presented using a modified PICOT format (patients, intervention, control, outcomes, and ongoing trials). ResultsIn three of the scenarios, consensus was reached and recommendations were for the use of consolidation durvalumab, but being respectful of potentially increased toxicity/reduced benefit in comparison to PACIFIC results (treatment of stage IIB inoperable, recurrent mediastinal disease, and residual gross disease post attempted surgical removal). There was a recommendation against using durvalumab in resected stage III disease with R1 or R0 margins, even if chemoradiation were considered. There was not consensus on the use of consolidation durvalumab in the setting of oligometastatic disease or in the setting of large cell neuroendocrine carcinoma or combined small cell carcinoma. ConclusionTreatment of ‘real-world’ lung cancer often involves chemoradiation in settings outside of stage III and eligible for the PACIFIC study. This paper offers recommendations in these scenarios based on a consensus approach.

P3.09-12 Molecular and Immunohistochemical Correlates of RB1 Inactivation in Small Cell Lung Carcinoma

Retinoblastoma (RB1) is a critical negative regulator of cell cycle progression, and serves as a tumor suppressor gene that is inactivated in many tumor types, including small cell lung carcinoma (SCLC). Because biallelic inactivation of RB1 has been observed in virtually all SCLC, loss of RB1 expression in the correct context is considered highly suggestive of SCLC or SCLC-like neuroendocrine carcinomas. However, the relationship between the genomic inactivation of RB1 and expression in SCLC has yet to be fully defined. Here, we characterize the genetic and immunohistochemical correlates of RB1 inactivation in SCLC. SCLC (n=57), and combined SCLC cases with a non-neuroendocrine component (CSCLC; n=5), that had undergone targeted next generation sequencing (NGS) (Oncopanel, 309-447 genes) were retrospectively identified. Designation of the molecular mechanism of RB1 inactivation was pursued by integrative analysis of RB1 variant type, variant allele fraction, and heterozygosity of the RB1 locus. RB1 protein status was interrogated in a subset of SCLC (n=25, 19 with biallelic inactivation) and CSCLC (n=2) by immunohistochemistry (IHC). 77% (44/57) of SCLC showed biallelic inactivation of RB1 by NGS, most commonly through a loss-of-function (LOF) variant and associated loss of heterozygosity (LOH, 65%). The most common mechanisms of RB1 genetic inactivation in these cases were nonsense (32%), frameshift (25%), and splice site (23%) variants, respectively. RB1 protein expression was lost in 89% (17/19) of SCLC with biallelic RB1 inactivation; the two remaining cases harbored RB1 splice site variants and displayed weak, patchy RB1 expression. Additionally, 80% (5/6) of SCLC without molecular evidence of RB1 biallelic inactivation showed loss of RB1 expression. Overall, 60% (3/5) of SCLC harboring splice site variants retained weak RB1 expression. 60% (3/5) of CSCLC showed molecular RB1 inactivation in all tumor cells. While one CSCLC showed loss of RB1 expression in both histologic components, the other tumor, which harbored a RB1 splice site variant, retained strong RB1 expression. Genetic inactivation of RB1 in SCLC may not be identified in ∼20% of cases via targeted NGS . While most SCLC with biallelic RB1 inactivation show loss of RB1 expression, retention of weak RB1 expression in SCLC does occur and may be associated with RB1 splice site variants. While additional investigation is needed to interrogate the functional and clinical significance of retained RB1 expression in SCLC, these data suggest that genetic RB1 inactivation does not always result in loss of protein expression, which may have implications for disease classification.

Combined small-cell lung carcinoma.

Currently, studies assessing combined small-cell lung carcinoma (C-SCLC) are relatively scarce and limited. Indeed the clinicopathological features, treatment, and prognosis of patients with C-SCLC have not been fully determined. The incidence of C-SCLC ranges from 5%–28% in different studies, which is related to the specimen types used. The clinical features of C-SCLC are characterized by the higher proportion of peripheral locations, earlier stage, and more opportunity to experience surgery. Surgery is more important for earlier stage C-SCLC. There have been no recent changes in the chemotherapy of C-SCLC, which is recommended by the treatment guidelines for SCLC, neither showing survival benefit from the 3-agent regimen. Meanwhile, the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in EGFR-mutated C-SCLC patients remains inconclusive. This review focuses on clinical and pathologic features, prognostic factors, and optimized treatment model in C-SCLC.

Clinicopathologic and Immunohistochemical Study of Combined Small Cell Carcinoma and Urothelial Carcinoma Molecular Subtype.

Muscle invasive bladder cancer, an aggressive disease with heterogeneous molecular profiles, has recently been subclassified into three major molecular subtypes -basal, luminal and "p53-like" urothelial carcinomas (UCas), which bear prognostic and therapeutic implication. Similar to breast cancer, basal and luminal subtype UCas are designated by basal (CK5/14) and luminal (CK20) markers. The "p53-like" subtype presents with wild-type p53 gene with upregulated p53 pathways and is implicated in chemoresistance. Urinary bladder is one of the most common primary sites of extrapulmonary small cell carcinoma (SmCC). Bladder SmCC frequently coexists with UCa; however, the relation of SmCC with specific UCa molecular subtypes has not been studied. The aim of this study is to investigate the clinicopathology and immunophenotypes of the combined SmCC and UCa molecular subtypes. A total of 22 combined SmCC and UCa cases were studied for the clinicopathology and immunohistochemical (IHC) profiles by luminal and basal cell markers as well as Her2/Neu and p53. Our results demonstrated that all the urinary bladder SmCCs were associated with high grade UCas. They were more commonly seen in older male patients with a smoking history and had a poor prognosis. Based on the reported molecular subtyping, the UCas could be immunohistochemically subclassified into luminal, basal, dual and null types, which showed different clinicopathologic and IHC features. Compared to non-SmCC associated UCa, the subtypes of UCa in the combined SmCCs and UCas were characterized by: 1) Although overall luminal type was still relatively more common in men, basal marker-expressing subtypes were significantly increased in incidence and were more common in women. 2) Her2/Neu overexpression was more commonly observed in luminal than basal cell marker-expressing UCas. 3) IHC overexpression of p53 was common in all the subtypes, with UCas and SmCCs sharing the same p53 expression pattern. Although limited by relatively a small number of cases, the results of this study will enhance our understanding of the combined SmCC and UCa entity and potentially lead to a future therapeutic management.