Combined SCLC Clinical And Pathological Aspects

Abstract

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 cells 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, and 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.

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Keywords: Chemotherapy; radiotherapy; combined small cell carcinoma. 

Contributions: FC, study design, collection and interpretation, article writing; SD, data collection and interpretation; SA, study design. All the authors read and approved the final version of the manuscript and agreed to be accountable for all aspects of the work.

Conflict of interest: We declare that there is no conflict of interest, in particular no financial funding potentially relevant to the contents of the manuscript.

Ethics approval: Our study was approved by the Ethics Committee of  Atatürk Chest Diseases Thoracic Surgery Training and Research  Hospital with the date of 11.06.2020 and decision number 677.

Funding: All support for this study came from institutional and departmental resources. This study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Received for publication: 7 February 2022. Accepted for publication: 31 May 2022.

Publisher's note: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors, and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Introduction

Lung cancer is one of the leading causes of cancer-related death for both genders worldwide. About 15% of all lung cancers are small-cell lung carcinoma (SCLC) cases [1].

Combined small cell lung carcinoma (CSCLC) is a histopathological variant of SCLC. Approximately 10-25% of SCLC cases are combined SCLC. The World Health Organization (WHO) defines CSCLC as small cell carcinoma with an extra component of any non–small cell histologic type. [2]. While adenocarcinoma (ADC), squamous cell carcinoma (SCC), large cell carcinoma (LCC), and large cell neuroendocrine carcinoma (LCNEC) components are more common among C-SCLC constituents, these are observed less frequently with giant cell carcinoma (GC) [3]. C-SCLC is diagnosed when ADC, SCC, or sarcomatoid cancer are coupled with SCLC, regardless of cell numbers. For C-SCLC diagnosis, however, at least 10% LCC (or LCNEC) is required. The World Health Organization/International Association for the Study of Lung Cancer (WHO/IASLC) has divided SCLC into three subgroups pure, mixed, and combined small cell carcinomas [4].

In contrast to the recent advances in diagnostic techniques, the incidence of C-SCLC has had an increasing trend [5]. C-SCLC contains various NSCLC components. Therefore, it has significant differences from pure SCLC in terms of biological, clinical, molecular, and pathological aspects. Overall, SCLC is the most aggressive of the major types of lung cancer, with the worst long-term prognosis and survival rates [6]. C-SCLC staging, treatment, and follow-up are similar to those of SCLC. Currently, C-SCLC is treated with surgery, radiotherapy, and chemotherapy according to SCLC guidelines. Follow-up without treatment quickly results in death. C-SCLC cases have a better prognosis compared to individuals with pure small cell type cancer who benefit from surgery.

Due to the small number of studies and reports on C-SCLC; clinical aspects, optimized treatment models, and prognostic factors are not yet clear. Currently, studies evaluating combined small-cell lung carcinoma (C-SCLC) are relatively few and limited. Our study aimed to investigate the clinical aspects and prognostic factors of CSCLC, as well as the role of multimodality therapy.

Materials and Methods

After Ethics Committee approval, hospital records of histologically combined small cell lung cancer patients over 18 years of age admitted between January 2015 and December 2019 were retrospectively analyzed at Ankara Atatürk Chest Diseases and Chest Surgery Training and Research Hospital starting from January 2020. The demographic, clinical, and laboratory parameters, staging status,  treatment methods, and prognostic data of the patients were reviewed retrospectively. Between these years, 313 patients were diagnosed with small cell lung cancer, while 31 patients were diagnosed with combined small cell lung cancer. Staging includes positron emission tomography (PET) or PET/CT. Brain metastasis was assessed using magnetic resonance imaging (MRI) or computed tomography (CT).

As recommended by the International Association for the Study of Lung Cancer, limited-stage TNM is equivalent to stages I-III and comprehensive-stage TNM is equivalent to stage 4 [7]. The requirement for informed consent from the patients was waived due to the retrospective nature of the study. Confidentiality of patient data was maintained throughout the study.

Statistical analysis

In the descriptive statistics of the data, mean, standard deviation,  median minimum-maximum, frequency, and ratio values were used. The distribution of variables was measured with the Kolmogorov-Smirnov test. The Mann-Whitney U test was used in the analysis of quantitative independent data. The chi-square test was used for the analysis of qualitative independent data, and the Fischer test was used when the chi-square test conditions were not met. Cox regression (univariate-multivariate) and Kaplan Meier were used for survival analysis. SPSS 27.0 program was used in the analysis.

Results

The male/female ratio of our patients was 24/7, and the mean age was 59. The most common symptoms were shortness of breath, cough, chest pain, and fatigue. Most of the cases were diagnosed by bronchoscopic biopsy. In the histopathological examination, 15 cases were diagnosed with small cell + squamous cell, 9 cases with small cell + large cell, and 7 cases with small cell+adenocarcinoma (Table 1). Table 1 shows the patients' age, gender, smoking history,  symptoms, type of tumor, diagnosis methods, laboratory and treatment methods. The location of the tumor was predominantly the central and right upper lobe. 11 cases had limited disease and the remaining 20 cases had extensive disease. Areas of metastasis at diagnosis were contralateral lung (n=7), bone (n=6), brain (n=5), and liver (n=5). The mean follow-up period of the patients was 10 months (Table 2). Table 2 shows tumor characteristics, location, tumor stages,  molecular and pathological aspects, treatments applied, and survival durations. Age, gender distribution, chemotherapy (CT), and concomitant chemoradiotherapy CRT ratio did not differ significantly between the ex and the living groups (p>0.05). The radiotherapy (RT) rate of the ex-group was significantly (p=0.024) lower than that of the living group (Table 3). The rate of SCC, adeno additional malignancy did not differ significantly between the ex and the living groups (p>0.05). The large cell malignancy rate of the ex-group was significantly (p=0.015) lower than that of the living group (Table 3). There was no significant difference between the family history and smoking history ratio, smoking habit, diagnosis method, symptom distribution, neutrophil to lymphocyte ratio (NLR), C-reactive protein (CRP), and lactate dehydrogenase (LDH) values (p>0.05) of the ex and living groups (Table 3). Tumor central/peripheral ratio, tumor location, tumor SUV max value, tumor diameter, and metastasis area distribution did not differ significantly between the ex and surviving groups (p>0.05) (Table 4). The rate of extensive disease and metastasis of the ex-group was significantly higher (p=0.000,  p=0.000) than that of the living group (Table 4). The rates of pleural effusion, epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), reactive oxygen species (ROS), and CD 56  did not differ significantly (p>0.05) between the ex-group and the living group. The thyroid transcription factor 1 (TTF1) rate of the ex group was significantly (p=0.029) higher than that of the living group. The ratio of cytokeratin, chromogranin, and napkin did not differ significantly between the ex and the living groups (p>0.05) (Table 4). The surgical rate of the ex-group was significantly (p=0.023) lower than that of the living group. Surgical technique distribution,  chemotherapy, and targeted therapy rates did not differ significantly between the ex and the living groups (p>0.05) (Table 4). In predicting the survival duration in the univariate model; no significant efficacy (p>0.05) of age, gender, sequential chemotherapy, concomitant chemoradiotherapy (CRT), additional malignancy, family history,  smoking, diagnostic method, hemoptysis, cough, dyspnea, chest pain, NLR, CRP, tumor distribution, tumor location, tumor diameter, tumor SUV max, liver metastases, bone metastases, brain metastases, pleural metastases, pericardial metastases, spleen metastases, abdominal metastases, adrenal metastases, pleural effusion, EGFR, ALK, ROS, TTF1, CD 56, chromogranin, napkin, surgery, surgical technique, and targeted therapy were observed. In the univariate model, sequential RT, fatigue, LDH, stage, metastasis, contralateral lung metastasis, and chemotherapy were observed to be significantly efficient 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 respectively) (Table 5). Significant-independent efficacy of sequential RT, stage, and chemotherapy in predicting survival duration was observed in the multivariate model (p=0.015,  p=0.022, p=0.049) (Table 5).

Discussion

Combined SCLCs constitute 10% to 25% of all SCLC cases and are defined by a mixture of pure SCLC and adenocarcinoma, squamous cell, large cell, or sarcomatoid (spindle or giant cell) carcinoma, regardless of the amount of NSCLC [4,8]. The mean age of patients with C- SCLC, which is a histopathological variant of SCLC, is 59-64 [9,10]. The mean age of our patient group was 59,  which is in line with this.

C-SCLC patients are predominantly male, with rates ranging from 43% to 82.5% [11,12]. Similarly, the rate was 77.4% for our patient group. Smoking history is obvious in the etiology of C-SCLC. In the analysis performed by Luo et al., smoking history was 77.5%, which is similar to the rate in our analysis [10]. NSCLC components in C-SCLC are mainly squamous cell carcinoma and adenocarcinoma [13]. In our study, however, the predominant type was the squamous cell component. SCLC and large cell neuroendocrine carcinoma (LCNEC) include components of other types of lung cancer often described as combined SCLC. Large cell neuroendocrine carcinomas (LCNECs) and small cell lung carcinomas (SCLCs) are high-grade neuroendocrine carcinomas of the lung with very aggressive behavior and poor prognosis [14]. However, in our study, the large cell malignancy rate of the ex-group was significantly (p=0.015) lower than that of the living group.

Diagnosis in C-SCLC is mostly made with small samples obtained by bronchoscopic biopsy, transthoracic fine needle aspiration, and cytology. The reason for the low case rates may be due to the small sample size and limited cytological materials. In their study, Fraire et al. [15] concluded that the diagnosis rate of C-SCLC is affected by the size and integrity of the biopsy specimen, and the number of pathological sections. Our patient group was mostly diagnosed with bronchoscopic biopsy. The main clinical symptoms of C-SCLC are cough, dyspnea, and hemoptysis [16]. In our study,  dyspnea was the most prominent symptom. C-SCLC is usually centrally located (59.1%-86.4%). Luo et al. [5], found the imaging aspects of the central mass in 86.4% of cases. In our patient group,  the central location rate was 71%.

Due to the excellent agreement between the prognosis of SCLC  and the TNM stage, the International Association for the Study of Lung Cancer recommended the use of the TNM classification system for NSCLC and SCLC in the 7th issue of AJCC [17]. At admission, 60-70% of C-SCLC patients are in the extensive stage [18]. The rate of common disease was 64.5% in our patient group. In our study, the rate of extensive disease and metastasis in the ex-group was significantly higher (p=0.000, p=0.000) than that of the living group. Prognostic factors for C-SCLC are the primary stage [15] and the type of non-SCLC component [13]. PET-CT has a high sensitivity for staging SCLCs [19]. Although SCLC is sensitive to chemoradiotherapy, survival rates are extremely low due to its high spread rates. When Luo et al. [5] summarized the clinical data of 88 patients with CSCLC, they found the median OS of Stage III and IV patients to be 10 months and 7.8 months, respectively. Similarly, 64.5% of our patients were in the extensive disease group and the mean follow-up period was 10 months.

Several studies have been conducted to measure the prognostic value of TTF-1 for patients with SCLC. Disease-free survival and overall survival were found to be poor for patients with SCLC TTF-1 expression. The study by Yan et al. showed that TTF-1 predicted lower survival in SCLC, which strengthened the prognostic value of TTF-1 [20]. In our study, this result was similar to the literature. The TTF1 rate in the ex-group was significantly (p=0.029) higher than that of the living group. Epidermal growth factor receptor (EGFR) mutations are found in NSCLC. Such mutations are rarer in SCLC. Combined SCLC/adenocarcinoma may include EGFR mutations in patients with a slight smoking history. In some studies, EGFR mutations were found to be 15% in C-SCLC [21]. In our study, a positivity rate was found in 2 patients (7.6%) out of 26 patients whose EGFR was analyzed. Pleural effusion rate, EGFR rate, ALK rate, ROS rate, and CD 56 rate did not differ significantly (p>0.05) between the ex-group and the living group in our study.

Although C-SCLC is very sensitive to chemotherapy and radiotherapy, it relapses very quickly and becomes resistant to treatment within 1-2 years. C-SCLC is treated according to SCLC  guidelines with commonly used multimodality therapy (surgery,  radiotherapy, and chemotherapy). Patients in the limited stage are usually treated with combined treatment modalities, while chemotherapy is used in the extensive stage. Platinum-based regimens are preferred because of their long survival and high response rates. While the SCLC component of C-SCLC responds well to chemotherapy, the NSCLC component increases. For this reason, CSCLC is considered to be resistant to chemotherapy [22]. Studies have shown that surgical treatment, especially lobectomy, results in local control, and the survival rate is higher for these patients [23,24]. In line with this, the surgical rate in the ex-group was significantly (p=0.023) lower than that of the surviving group in our study.

Lactate is upregulated by LDH in tumor cells. It is known that a high LDH level is a poor prognostic factor in small-cell lung carcinoma. Elevated LDH levels can be associated with tumor mass and amount. For our patients, LDH levels were high in the ex-group and provided a poor prognosis. These results are consistent with previous reports [25].

In our study, significant efficacy of sequential RT, fatigue, LDH,  stage, metastasis, contralateral lung metastasis, and chemotherapy in predicting survival time in a univariate model was observed (p=0.000, p=0.050, p=0.011, p=0.004, p=0.004, p=0.045, p=0.009, respectively). In our study, significant-independent efficacy of sequential RT, stage, and chemotherapy was observed in predicting survival duration in a multivariate model (p=0.015, p=0.022,  p=0.049).

Combined SCLC histology is uncommon, accounting for 10%  to 25% of all SCLC cases. C-SCLC is a kind of mixed carcinoma that has received little research attention. It's critical to figure out what type of mixed histology you have because it can alter your chances of survival.

Small cell lung cancer is treated similarly to mixed-type small cell lung cancer in terms of diagnosis, treatment, and follow-up. High TTF1 and LDH levels, as indicated in our study, are poor prognostic markers, as are the advanced stage and the existence of metastases. Survival is highly dependent on the stage of the disease, radiation, and chemotherapy. To better understand clinical behavior and prognosis, multicenter research is required.

Our study has several limitations, including a single-center design, retrospective analysis, and a small sample size. However,  these observations should be developed in larger-scale studies.

In the future, we expect that novel chemotherapeutic medications and targeted agents will have an impact on response rates and survival in this patient group.

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