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Abstract
This article describes a case of a man in his early 40s who was diagnosed with pulmonary pleomorphic carcinoma (PPC). PPCs are rare and aggressive forms of lung cancer. Chemotherapy is of limited efficacy. We present a case that has seemingly recurred shortly after adjuvant chemotherapy and immunotherapy following an R0 resection for localised disease. Biopsy however was negative for recurrence. PPCs may bear actionable mutations and tyrosine kinase inhibitors may be used when appropriate. Immunotherapy with or without chemotherapy is emerging as the mainstay for metastatic disease despite a lack of evidence from randomised clinical trials.
- Lung cancer (oncology)
- Chemotherapy
- Immune Checkpoint Inhibitors
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Background
Pulmonary sarcomatoid carcinomas constitute a rare subset of tumours, comprising approximately 1% of non-small cell lung carcinoma (NSCLC) cases.1 Continued from 2004 and 2015 WHO classification,2 the 2021 WHO classification of NSCLC groups pulmonary pleomorphic carcinomas (PPC)3 into a type of sarcomatoid carcinoma, which also includes giant cell or spindle cell morphologies.
PPC typically exhibits an aggressive clinical course and poses challenges in differential diagnosis with other primary and secondary lung malignancies. Clinical characteristics of PPCs lack specificity compared with other NSCLC subtypes. Surgical resection proves to be the most effective treatment but is best when the disease is localised.4–6 Systemic chemotherapies are marginally effective when these cancers are at an advanced stage. In a multicentric study, patients with advanced lung sarcomatoid cancer receiving first-line platinum-based chemotherapy showed a high rate of resistance.7 Another study highlighted that some patients are refractory to first-line chemotherapy with the sarcomatoid subtype being an independent factor for associated early disease progression.8 There is a need for better treatment options for these rare tumours. In the targeted therapy and immunotherapy era, molecular profiling is increasingly incorporated into clinical practice, however, the efficacy of targeted therapy and immunotherapy for PPC is yet to be proven. Through this case, we illustrate the need to manage this disease in a multidisciplinary fashion, with surgical resection as the first line of therapy whenever possible. In addition, we stress the need for next-generation sequencing and PD-L1 testing to gauge the efficacy of molecular targeted and immune checkpoint inhibitor therapy.
Case presentation/investigations/differential diagnosis/treatment
A man in his early 40s with no significant medical history initially presented to our emergency department (ED) a year ago with chest pain and shortness of breath of insidious but progressive onset over several weeks. Physical examination and routine laboratory workup were unremarkable. Chest X-ray revealed a right pneumothorax and a right upper lobe lung mass. Further imaging with a CT of the chest with intravenous contrast revealed a large right-sided pneumothorax with minimal leftward displacement of the mediastinal structures and a 3.4 cm dense mass abutting the posterior right upper lobe pleura with cystic necrosis highly suspicious for malignancy. A chest tube was placed in the ED which led to improvement of the pneumothorax, chest pain and shortness of breath.
CT-guided biopsy of the mass of the right upper lung showed a poorly differentiated non-small cell carcinoma. Sections of the biopsy demonstrated predominantly necrotic debris with scattered viable tumour cells within a desmoplastic stroma. The tumour cells are large and pleomorphic with moderate-to-large amounts of eosinophilic cytoplasm and focal rhabdoid features. Scattered tumour giant cells are noted as identifiable mitotic figures (figure 1A,B). The immunophenotype supports the diagnosis of carcinoma but was otherwise non-specific, with the tumour cells expressing CK7 and CK AE1/3 but negative for TTF1, Napsin A, P40, SOX10 and CD45. As this immunophenotype is not specific, the tumour cannot be further characterised and TTF-1 negative adenocarcinoma versus other poorly differentiated non-small cell carcinoma would be within the differential. PD-L1 staining using the 22C3 antibody was positive for high PD-L1 expression with a tumour proportion score of 90%. A PET scan before mediastinal staging (figure 2A) revealed a solitary peripheral intensely hypermetabolic pleural-based, lobulated right upper lobe mass. There was no definitive FDG PET evidence of regional or distant metastasis. MRI of the head with and without contrast preoperatively revealed no intracranial metastasis.
H&E staining of resected pulmonary pleomorphic carcinoma. Carcinoma with large pleomorphic tumour cells and a rhabdoid appearance in (A), 40× and a focal epithelioid appearance in (B), 20×.
PET image showed a solitary peripheral intensely hypermetabolic pleural-based, lobulated right upper lobe mass (A, arrowhead, prior to mediastinal staging and surgical resection). Hypermetabolic peripheral left upper lobe (arrow) and left hilar lymph nodes (arrowhead) suggested metastatic disease (B, after adjuvant immunotherapy). Bronchoscopy and transbronchial biopsy of the left upper lobe, and endobronchial ultrasound with needle biopsy of the left hilar, subcarinal node showed no viable tumour.
An endobronchial ultrasound with biopsy to stage the mediastinum was negative for carcinoma in the left level 4 paratracheal, right level 4, level 7 and right level 10. He underwent right robotic upper lobectomy, and mediastinal lymph node dissection. Postoperative pathology confirmed a pleomorphic (sarcomatoid) carcinoma. The surgical resection specimen had negative margins and all nodes were negative, the cancer was staged as AJCC8 pT3pN0 (stage IIb) due to invasion into the chest wall and muscle.
The patient’s performance status was an ECOG 0. He was initially planned for four cycles of chemotherapy with cisplatin/docetaxel but he received only one cycle. The patient had hearing changes which proved to be transient, nausea, vomiting and diarrhoea after the first dose of chemotherapy despite adequate medication. Following severe side effects with chemotherapy, it was decided to stop chemotherapy and switch to atezolizumab immunotherapy for consolidation based on high PD-L1 expression in the tumour. He completed 11 cycles of atezolizumab every 4 weeks when it was decided to stop before the last cycle as he was having severe systemic inflammation with fever, chills, night sweats, weight loss, joint pain and diarrhoea with no other identifiable cause. He was treated with a short course of steroids and the inflammation resolved. Throughout treatment, a CT scan was performed once every 3 months without new lesions. However, the CT scan approximately 1 year after adjuvant treatment, 2 months after stopping immunotherapy, showed a new lesion suggestive of disease progression. The patient was noted to have developed a new 10 mm anterior basal left lower lobe pulmonary nodule on the CT of the chest. A repeat PET seemed to suggest disease progression in the right middle lobe, left upper lung, left hilar and the mediastinal node (figure 2B). Repeat bronchoscopy of the left upper lobe with transbronchial biopsy, endobronchial ultrasound and sampling of hilar, subcarinal node all failed to show viable tumour. A repeat CT scan showed a resolution of lymphadenopathy and the left upper lobe lesion on the prior CT. This was considered a pseudoprogression and the patient was started back on surveillance.
Next-generation sequencing (NGS) was sent for both blood (liquid) and tissue harvested during lobectomy. While liquid biopsy did not reveal any mutations reflecting low circulating tumour DNA shed, tissue NGS showed RBM10, TP53, NF2, CHD2, CDKN2A and FLCN allele frequency ranged from 6.9–45.7%. Tumour mutation burden was high 11.1/Mb (89th percentile) and mismatch repair status was proficient. No targetable mutation was found in EGFR or MET or others.
Discussion
Pulmonary pleomorphic carcinoma is a rare entity. The sarcomatoid component of these tumours is believed to arise from carcinoma cells during carcinogenesis progression through the activation of an epithelial mesenchymal transition programme, leading to sarcomatous transformation or metaplasia (conversion paradigm).9
Patients affected by these tumours, typically are tobacco smokers and commonly present with symptoms. In a retrospective study,5 the male-to-female ratio was 19:3 and the age at diagnosis was 68.3±10.1 years (range 51–94). Symptoms were seen in 16 patients (72.7%) and common symptoms were haemoptysis (7 cases) and cough (6 cases). Fever, pain, dyspnoea and body weight loss were also seen. Six patients (27.3%) had no symptoms but were referred to hospital with lung nodules detected on chest X-rays.
Tumours tend to be large, more frequently located peripherally than centrally, and exhibit strong uptake on FDG PET CT scans as illustrated in our case. Distant metastases are frequent, often involving atypical visceral locations.
PPCs are difficult to treat. Surgery provides the best chance for survival especially in localised stage,4–6 HR ranged from 0.120 to 0.484. Radiation therapy is marginally beneficial (HR 0.801, p<0.04).5 These tumours are generally thought to be resistant to conventional chemotherapy. A phase II study from Japan used carboplatin, paclitaxel and bevacizumab for metastatic disease.10 There are no specific guidelines for treating PPCs.
Our patient is young. He was initially planned four cycles of conventional cytotoxic agents containing a platinum and a taxane, which is reportedly more effective in the phase 2 study.11 However, the patient developed severe toxicity post cycle 1 of cisplatin doublet requiring a change in therapy plans. The patient had 90% positivity of PD-L1 making immunotherapy a viable option per IMpower 010 study for stage Ib-IIIa post resection in patients expressing 1% or more PD-L1.11 The patient was offered enrolment in the ALCHEMIST trial with pembrolizumab but the patient failed to enrol during the enrolment window period. On completion of one cycle of adjuvant chemotherapy and 11 months of single-agent anti-PD-L1 immune checkpoint inhibitor with atezolizumab for a tumour expressing a very high level of PD-L1, at the cost of some mild-to-moderate cytokine release syndrome needing a short course of corticosteroid, cancer seemed to have progressed 2 months after the last cycle of immunotherapy. Given the short period lapsed and reported pseudoprogression12 after immunotherapy for PPCs, a biopsy was deemed necessary to verify progression. No recurrent tumour was seen.
NSCLC, especially adenocarcinomas subtype often contains actionable mutations as oncogenic drivers. Small molecule inhibitors developed against the driver that is approved by the US Food and Drug Administration as first-line therapy include EGFR, ALK, ROS, RAF, RET, MET, NTRK1-3, and in the second-line setting for KRAS G12C and HER2. Due to the rarity, however, information regarding the molecular profile of PPCs only started to emerge. Liu et al discovered via NGS high-frequency MET exon 14 mutation and its sensitivity to crizotinib.13 Pécuchet et al attempted molecular classification of pulmonary sarcomatoid tumours by doing whole exosome sequencing of 15 tumours of their own plus the 10 samples published by Liu et al.14 Two signatures were discovered. Signature 4 is characterised by tobacco-induced DNA injury with KRAS, MAP2K1 activation.14 These tumours express high PD-L1 and have a good chance of responding to immune checkpoint inhibitors. Signature 2-3-13 related to APOBEC activation (apolipoprotein B mRNA editing enzyme). These tumours often have MET, EGFR, IDH1 mutation.14 In addition, DNA homologous recombination repair pathway is defective due to BRCA1/2 and BAP1 mutation.14 These tumours could be treated with platinum, or small molecular targeting therapy. Nagano et al15 used NGS to analyse the genomic and transcriptomic profiles of PPCs. DNA and RNA samples from 78 specimens were obtained from 52 patients with PPCs and focused on 15 PPC cases to compare gene alterations, tumour mutation burden (TMB), RNA expression and PD-L1 expression between the epithelial and sarcomatoid components within tumours. Genomic alterations in six cases of primary tumours and their corresponding metastatic tumours were also analysed. KRAS mutations (27%) were the most common driver mutations, followed by EGFR (8%) and MET (8%) mutations. Both epithelial and sarcomatoid components harboured these activating driver mutations, with no significant differences in CD274 expression or TMB observed between them. PD-L1 expression was notably higher in the sarcomatoid component compared with the epithelial component in some cases. The study revealed that primary and metastatic tumours shared common oncogenic mutations, such as KRAS and TP53 mutations. Additionally, they identified specific alterations, including NOTCH4 mutations, in metastatic regions. These findings were corroborated by earlier reports on the presence of EGFR, KRAS and MET/FGFR alterations.16 These findings suggest that therapies targeting activating driver mutations may be beneficial for patients with PPC. A trial of savolitinib and osimertinib in these patients showed the inhibitors could be equally effective.17 18
For our patient, high PD-L1 expression of 90% and TMB (>11/Mb) predict a good chance of response to immunotherapy with anti-PD1 or PD-L1 like those reported in the case series19 20 or pooled analysis.21 The excellent immune response during adjuvant atezolizumab suggested that his disease would have little chance if any to recur although time will tell. In case the tumour recurs, a clinical trial, if available, would be preferred. A taxane-containing regimen with an immune checkpoint inhibitor will be a reasonable choice if clinical trial is not an option.
Learning points
Pulmonary pleomorphic carcinomas (PPCs) are rare and aggressive.
PPCs do not respond to radiation therapy well and are perceived as chemotherapy resistant.
Molecular profiling provides options for targeted treatment and clinical trials.
PPCs seem to respond to immune checkpoint inhibitors well based on small retrospective observations or pooled analysis.
Ethics statements
Patient consent for publication
Acknowledgments
We would like to thank the Markey Cancer Center Research Communication Office Donna F Gilbreath for editorial assistance.
Footnotes
Contributors The following authors were responsible for drafting of the text, sourcing and editing of clinical images, investigation results, drawing original diagrams and algorithms and critical revision for important intellectual content: TD, KA, ZH. The following authors gave final approval of the manuscript: TD, KA, ZH.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.