Surgical resection reveals combined small-cell lung carcinoma and adenocarcinoma with dual epidermal growth factor receptor and anaplastic lymphoma kinase alterations following neoadjuvant chemotherapy: A rare case

Abstract

Combined small-cell lung carcinoma is a rare and heterogeneous lung cancer characterized by the coexistence of small-cell and non-small-cell components. Concurrent epidermal growth factor receptor mutation and anaplastic lymphoma kinase rearrangement in combined small-cell lung carcinoma is extremely uncommon and presents diagnostic and therapeutic challenges. We report a 63-year-old man presenting with cough and right-sided chest pain. Imaging revealed a right lower lobe mass with mediastinal lymphadenopathy. Initial biopsy showed adenocarcinoma without actionable mutations. Following a limited response to neoadjuvant chemotherapy, right lower lobectomy was performed. Histopathological examination revealed combined small-cell carcinoma and adenocarcinoma, while molecular analysis identified concurrent epidermal growth factor receptor exon 19 deletion and anaplastic lymphoma kinase rearrangement. Lymph nodes were negative for metastasis. Postoperative targeted therapy was initiated, and follow-up imaging showed no evidence of recurrence. This case highlights tumour heterogeneity and the importance of comprehensive pathological and molecular evaluation in guiding personalized therapy.

Introduction

Lung cancer is broadly classified into small-cell lung carcinoma (SCLC) and non-SCLC (NSCLC), which differ in biology and management. ¹ However, histologic heterogeneity within individual tumours may complicate diagnosis and treatment selection. Combined SCLC (C-SCLC) is a rare subtype characterized by the coexistence of SCLC and NSCLC components, most commonly adenocarcinoma. ² It is more frequently identified in resection specimens than in small biopsies, reflecting the limitations of limited tissue sampling in detecting mixed histology.^3,4

Driver alterations such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements are well described in lung adenocarcinoma but are uncommon in SCLC.^5,6 Their coexistence within C-SCLC is exceptionally rare and poses therapeutic uncertainty.^7,8 Although surgery has a limited role in advanced SCLC, it may provide definitive histopathologic diagnosis and enable comprehensive molecular profiling in selected patients.^9,10

We report a case of surgically resected C-SCLC with concurrent EGFR exon 19 deletion and ALK rearrangement identified following a limited response to neoadjuvant chemotherapy, highlighting the diagnostic value of complete tumour evaluation.

Case presentation

A 63-year-old Asian man presented on 19 June 2025, with a 3-month history of intermittent non-productive cough and progressive right-sided chest discomfort. He denied haemoptysis, weight loss, or dyspnoea. His medical history was significant for well-controlled hypertension. He had never smoked and reported a maternal history of lung cancer. Physical examination revealed no palpable lymphadenopathy or abnormal breath sounds.

Contrast-enhanced chest computed tomography (CT) demonstrated a 3.45 × 2.43 cm lobulated mass in segment 6 of the right lower lobe adjoining the lateral pleura. Enlarged ipsilateral mediastinal and hilar lymph nodes were noted, including right paratracheal (0.8 cm), subcarinal (1.1 cm), and peri-bronchial nodes (1.3 cm; Figure 1(a)–(d)). No pleural effusion was identified. Staging workup, including abdominal ultrasonography, contrast-enhanced brain CT, and bone survey, revealed no distant metastases.

Figure 1.

Radiological examination results. (a–d) Baseline contrast-enhanced chest CT before neoadjuvant chemotherapy axial lung window (mass level), mediastinal window (station 4 lymph node level), mediastinal window (station 7 lymph node level), mediastinal window (station 10 lymph node level), respectively, with red arrows indicating the corresponding lesions. (e–h) Contrast-enhanced chest CT after three cycles of neoadjuvant chemotherapy axial lung window (mass level), mediastinal window (station 4 lymph node level), mediastinal window (station 7 lymph node level), and mediastinal window (station 10 lymph node level), respectively, with red arrows indicating the corresponding lesions.

CT: computed tomography.

The patient underwent CT-guided transthoracic needle biopsy of the pulmonary mass and endobronchial ultrasound-guided transbronchial needle aspiration of mediastinal lymph nodes. Histopathologic examination of the lung biopsy specimen demonstrated adenocarcinoma with glandular architecture. Molecular testing performed on the biopsy sample showed wild-type EGFR, negative ALK expression, and negative PD-L1 expression. Based on radiologic and pathologic findings, the tumour was staged clinically as T2aN2bM0 (stage IIIB).

Neoadjuvant chemotherapy with pemetrexed and carboplatin was initiated and administered every 21 days for three cycles. The treatment was well tolerated without significant complications. Post-treatment CT imaging demonstrated a residual mass measuring 3.3 × 2.4 cm with persistent mediastinal lymphadenopathy and no significant radiologic reduction in nodal size (Figure 1(e)–(h)). Given the limited radiologic response and absence of distant disease, the case was reviewed in a multidisciplinary tumour board, and surgical resection was recommended.

On 1 October 2025, the patient underwent video-assisted thoracoscopic surgery (VATS) right lower lobectomy. Intraoperatively, pleural adhesions were encountered, requiring pulmonary decortication. Due to technical difficulty in achieving adequate lymph node dissection via VATS, the procedure was converted to open thoracotomy. Systematic lymph node dissection was performed, including stations 4, 7, 8, 9, 12, and 13. The postoperative course was uneventful.

Gross examination of the resected specimen revealed a 4.3 × 3.5 × 3 cm firm, grey–white mass with focal black pigmentation and areas of necrosis (Figure 2). The surrounding lung parenchyma appeared unremarkable.

Figure 2.

Gross specimen of the resected right lower lung showing a firm, grey–white mass with focal black pigmentation and areas of necrosis, measuring 4.3 × 3.5 × 3 cm (circled in red).

Microscopic evaluation demonstrated two morphologically distinct tumour components. The predominant component, comprising ~90% of the tumour, consisted of sheets of small cells with scant cytoplasm, finely granular (“salt-and-pepper”) chromatin, inconspicuous nucleoli, frequent mitoses, and areas of necrosis—features consistent with small-cell carcinoma. The second component, accounting for ~10% of tumour volume, displayed glandular and papillary architecture with pleomorphic nuclei, prominent nucleoli, and moderate eosinophilic cytoplasm, consistent with adenocarcinoma (Figure 3(a)).

Figure 3.

Histopathological and immunohistochemical findings reveal both SCLC at the left side of each slide (black arrows) and AdenoCa components at the right side of each slide (white arrows). (a) Haematoxylin and eosin staining showing small-cell (black arrows) and AdenoCa components (white arrows; H&E, ×20 objective). (b) Cytokeratin AE1/AE3 immunostaining demonstrating focal positivity in the small-cell component (black arrows) and diffuse positivity in the AdenoCa component (white arrows; IHC, ×20 objective). (c) CD56 immunostaining showing positivity in the small-cell component (black arrows) and negativity in the AdenoCa component (white arrows; IHC, ×20 objective). (d) Synaptophysin immunostaining showing negativity in both components (IHC, ×20 objective). (e) TTF-1 immunostaining demonstrating diffuse positivity in the small-cell component (black arrows) and focal positivity in the AdenoCa component (white arrows; IHC, ×20 objective). (f) Chromogranin immunostaining showing positivity in the small-cell component (black arrows) and negativity in the AdenoCa component (white arrows; IHC, ×20 objective). (g) Ki-67 immunostaining demonstrating a high proliferation index (~80%) in the small-cell component (black arrows) and a low proliferation index (<10%) in the AdenoCa component (white arrows; IHC, ×20 objective).

AdenoCa: adenocarcinoma; IHC: immunohistochemistry; SCLC; small-cell lung carcinoma; TTF-1: thyroid transcription factor-1.

Immunohistochemical analysis further characterized the tumour. The small-cell component showed positivity for CD56 and chromogranin, diffuse thyroid transcription factor-1 (TTF-1) expression, and a high Ki-67 proliferation index of ~80%. The adenocarcinoma component demonstrated diffuse cytokeratin AE1/AE3 positivity, focal TTF-1 expression, and a low Ki-67 index of ~<10%, while being negative for neuroendocrine markers (Figure 3(b)–(g)). These findings established a definitive diagnosis of C-SCLC and adenocarcinoma.

Comprehensive molecular analysis was performed on the resected tumour specimen. EGFR mutation testing was conducted using real-time polymerase chain reaction with Scorpion amplification refractory mutation system technology, which identified an exon 19 deletion. ALK rearrangement was evaluated by immunohistochemistry using the D5F3 clone, which demonstrated strong diffuse cytoplasmic positivity consistent with ALK rearrangement. PD-L1 expression was assessed using the SP263 clone and showed tumour proportion score <1%. All dissected lymph nodes were free of metastatic involvement. Surgical margins were negative.

Postoperatively, targeted therapy was initiated with gefitinib (250 mg once daily) and alectinib (600 mg twice daily). Follow-up contrast-enhanced chest CT at 2 weeks and 3 months after surgery demonstrated no evidence of residual or recurrent disease (Figure 4(a) and (b)). Following the CT follow-up findings, the patient continued treatment with alectinib and gefitinib in combination with chemotherapy. At the most recent follow-up, the patient remained asymptomatic and continued therapy under close surveillance.

Figure 4.

Radiological examination results. (a) Contrast-enhanced chest CT 2 weeks after surgery, axial lung window. (b) Contrast-enhanced chest CT 3 months after surgery, axial lung window. Red arrows indicating the previous lesion mass location.

CT: computed tomography.

Discussion

C-SCLC is a heterogeneous entity characterized by the coexistence of small-cell and non-small-cell components within the same tumour. ² It is more often diagnosed in resected specimens than in small biopsies, reflecting the challenges of adequately sampling mixed histology tumours.^3,4 In this case, preoperative biopsy identified adenocarcinoma without alterations, whereas surgical resection revealed a predominant small-cell component with a minor adenocarcinoma component and dual driver mutations. This discrepancy illustrates the risk of underrecognizing histologic heterogeneity when relying on limited tissue samples. ¹⁰

The limited radiologic response to platinum-based neoadjuvant chemotherapy prompted surgical exploration within a multidisciplinary framework. Resection provided definitive pathologic staging and revealed that the adenocarcinoma component accounted for ~10% of tumour volume—likely insufficiently sampled preoperatively. These findings reinforce the need to consider mixed histology when clinical behaviour is discordant with the initial diagnosis and treatment plans.^4,10

While surgery is not routinely recommended for advanced NSCLC, selected patients with localized disease and limited response to systemic therapy may benefit from resection within a multimodal strategy.^11,12 In this case, complete resection enabled comprehensive molecular characterization and directly informed postoperative targeted therapy. C-SCLC is a heterogeneous tumour containing both small-cell and non-small-cell components, which may be underrecognized in limited biopsy samples. In this case, biopsy identified adenocarcinoma, while resection revealed predominantly small-cell carcinoma with a minor adenocarcinoma component and concurrent EGFR and ALK alterations, highlighting intratumoural heterogeneity. Limited response to chemotherapy led to surgery, which enabled definitive staging, comprehensive molecular profiling, and informed targeted postoperative management within a multidisciplinary approach.^2,12 The identification of rare composite tumours with targetable dual alterations is becoming increasingly important in precision oncology.

SCLC is typically characterized by positive immunoreactivity for neuroendocrine markers, including Synaptophysin, Chromogranin, and CD56. However, in the present case, Synaptophysin was negative in the small-cell component. Previous studies have demonstrated that up to 15%–20% of SCLC cases may be negative for both Synaptophysin and Chromogranin, while most retain positivity for CD56, which is considered the most sensitive neuroendocrine marker. ¹³ Therefore, the diagnosis of SCLC should be based on a panel of immunohistochemical markers interpreted in conjunction with characteristic morphological features, rather than reliance on a single immunostaining.

The detection of concurrent EGFR exon 19 deletion and ALK rearrangement further emphasizes the biological complexity of C-SCLC. Although EGFR mutations and ALK alterations are well-established oncogenic drivers in lung adenocarcinoma, they are rarely observed in SCLC.^5,6 Their coexistence, typically considered mutually exclusive in NSCLC, suggests significant intratumoural heterogeneity or clonal divergence from a common progenitor.^7,8 In this context, prospective evidence to guide optimal management of such dual-driver tumours remains lacking, and treatment decisions must therefore rely on individualized, multidisciplinary assessment.

Gefitinib, a tyrosine kinase inhibitor (TKI), has demonstrated efficacy in tumours harbouring EGFR mutations, while alectinib, an ALK inhibitor, is effective in ALK-rearranged tumours. Given the absence of a standardized treatment approach for tumours with concurrent EGFR and ALK alterations, emerging evidence suggests that combined EGFR-TKI and ALK inhibitor therapy may provide clinical benefit in selected patients. In the present case, the decision to initiate gefitinib in combination with alectinib was based on multidisciplinary team discussion and tailored to the patient’s molecular profile.^14,15 Considering the potential for drug–drug interactions and overlapping toxicities, the patient is being closely monitored at each follow-up visit.

Conclusion

This case highlights the limitations of small biopsy specimens in capturing tumour heterogeneity, particularly in combined small cell lung carcinoma. Surgical resection played a critical role in establishing a definitive diagnosis and enabling comprehensive molecular characterisation. The identification of concurrent EGFR and ALK alterations informed a personalised treatment strategy. Multidisciplinary collaboration was essential in integrating clinical, radiological, pathological, and molecular findings. Comprehensive diagnostic evaluation, including adequate tissue sampling and molecular profiling, is essential for optimal management of rare composite tumours.