Metastatic lung pleomorphic giant cell carcinoma treated with multimodality systemic anti-cancer treatment, a two-year journey: A case report.

1
Introduction
Pleomorphic Giant Cell Carcinoma (PGCC) of the lung is a distinct, rare, and highly aggressive subtype of poorly differentiated non-small cell lung carcinoma (NSCLC) [1,2]. It represents a morphologically unique entity defined by the presence of markedly pleomorphic and multinucleated giant tumor cells exhibiting abundant eosinophilic cytoplasm and atypical mitotic figures [[3], [4]]. Histologically, these features reflect extreme cellular anaplasia and a loss of conventional epithelial differentiation, which contribute to the tumor's rapid progression and resistance to therapy.
According to the World Health Organization (WHO) classification of thoracic tumors [5], PGCC is classified within the group of sarcomatoid carcinomas, a heterogeneous category of poorly differentiated NSCLCs that display both epithelial and mesenchymal features. This category includes spindle cell carcinoma, giant cell carcinoma, carcinosarcoma, and pulmonary blastoma. Among these, PGCC is distinguished by its predominance of pleomorphic and multinucleated giant cells with minimal glandular or squamous differentiation, indicating a high-grade, undifferentiated histology [[3], [4], [5]].
In terms of incidence, PGCC of the lung is exceedingly uncommon, accounting for less than 0.3–1 % of all lung cancers [[6], [7], [8]]. Because of its rarity and the challenges in histopathologic recognition—often requiring immunohistochemical confirmation—its true frequency may be underestimated [8]. The tumor tends to occur predominantly in older male smokers and is more frequently observed in geographic regions with a high background incidence of lung cancer, particularly those with elevated exposure to tobacco smoke, asbestos, and industrial pollutants [9,10].
The prognosis for patients with PGCC is notoriously poor, with a median survival significantly shorter than that of other NSCLC subtypes. Even with multimodal treatment—including surgical resection, chemotherapy, and radiotherapy—most patients present with advanced-stage disease and demonstrate early metastasis and high recurrence rates. Reported five-year survival rates are typically below 10 %, emphasizing its extremely aggressive clinical course and limited response to conventional therapies [9,11,12].
The primary risk factors for the development of PGCC include heavy smoking, exposure to environmental carcinogens such as asbestos and radon, and a history of chronic lung diseases like chronic obstructive pulmonary disease (COPD). Genetic predisposition and previous radiation therapy to the chest have also been implicated as potential contributing factors [10,13]. PGCC predominantly affects older adults, with the median age of diagnosis typically ranging from 60 to 70 years [13,14].
We present a case of an adult man with stage IV, PD-L1–negative PGCC managed through a sequential multimodal treatment approach.

2
Case presentation
A 50-year-old gentleman with no known comorbid conditions, presented to emergency department in May 2021, with a generalized tonic-clonic seizure. He has a lifelong history of heavy smoking, along with a family history of breast cancer in his sister and hepatocellular carcinoma in his mother.
After immediate resuscitation, he had several investigations including computed tomography (CT) and magnetic resonance imaging (MRI) of the brain. The scans showed a well-circumscribed lesion in the left temporo-occipital region with surrounding edema, along with a smaller lesion in the right insular cortex (Fig. 1A). His chest X-ray demonstrated multiple lobulated mass lesions in both lung fields, with the largest lesion localized in the right hilar region. Whole-body contrast-enhanced CT (PAN-CT) revealed a right perihilar soft tissue mass, highly suggestive of a primary lung malignancy, accompanied by multiple bilateral metastatic pulmonary nodules and enlarged lymph nodes in the left hilar and upper left abdominal regions. Additionally, multiple hypodense metastatic lesions were detected in the liver. Positron emission tomography with fluorodeoxyglucose (FDG-PET) confirmed the findings observed on CT; however, the hepatic lesions were below the resolution threshold of the PET scan (Fig. 2). CT guided biopsy was performed which showed pulmonary pleomorphic giant cell carcinoma.
The patient underwent a left temporoparietal craniotomy with resection of the left posterior temporal lesion, followed by stereotactic radiotherapy targeting the postoperative tumor cavity and the smaller intracranial lesions. Histopathological sections showed tumor with bizarre looking giant cells, pleomorphic nuclei, and prominent nucleoli (Fig. 3). The cells were arranged in an infiltrative pattern. Most of the cells had clear cytoplasm. By immunohistochemistry (Fig. 4), tumor was positive for CK AE1/AE3, CK7, CK19, CK8/18, S100P, GATA3 and inhibin. Meanwhile, CK20, PAX8, P63, P40, TTF-1, Napsin-A, ALK (5A4), PDL-1, Androgen, Calretinin, WT-1, CEA, CDX2, OCT3/4, Arginase, HepPar, B-HCG, SALL4 and CD117 were negative. The primary site was concluded to be most likely of pulmonary origin; however, immunohistochemical findings of positive (CK7, S100P, CK19, CK8/18, GATA3, Inhibin) were confusing and widened the differential diagnosis to include: urothelial carcinoma, adrenal cortical carcinoma and upper GI/pancreatobiliary tract. Clinical and radiologic correlations were required to specify the primary site as lung. Additionally, next-generation sequencing (NGS) did not identify any actionable genetic mutations.
After discussion of the case in a thoracic multidisciplinary team (MDT) meeting in June 2021, the patient was initiated on a regimen of four cycles of nivolumab and ipilimumab immunotherapy, which continued until December 2021. Interim FDG-PET (Fig. 2A) demonstrated a favourable therapeutic response. Subsequently, the patient received a single dose of maintenance nivolumab; however, by February 2022, follow-up FDG-PET imaging (Fig. 2B) indicated disease progression, characterized by persistent metabolic activity in the right and left hilar regions, as well as newly identified metastatic lymph nodes in the subcarinal, left paratracheal, and abdominal regions. Additionally, a new metastatic lesion was detected in the duodenal wall.
As a second-line treatment, the patient was commenced on the MAID chemotherapy regimen (Ifosfamide, Mesna, Doxorubicin, and Dacarbazine) on March 8, 2022. Following the completion of three cycles by the end of April 2022, FDG-PET scan revealed partial morpho-metabolic regression across several sites, including the right hilar region (presumed primary lesion), mediastinal lymph node metastases, bilateral pulmonary metastases, abdominal metastatic lymph nodes, and the duodenal wall lesion (D2). No evidence of new or progressive disease was observed. The patient subsequently received two additional cycles of the MAID protocol, achieving stable disease status for an additional six months, as confirmed by PET imaging in September 2022 (Fig. 2C).
However, in November 2022, brain imaging revealed disease progression, which was managed with stereotactic radiosurgery (SRS) (Fig. 1B). By December 2022, imaging demonstrated further progression in the right hilar and subcarinal regions, along with the emergence of new metastatic deposits in the mesenteric root lymph nodes (Fig. 2D).
Consequently, third-line therapy with Carboplatin and Paclitaxel was initiated, administered over six cycles, with the final dose administered on May 9, 2023. A subsequent PET scan in May 2023 (Fig. 2E) showed a partial metabolic response in the hilar and mesenteric lymph nodes; however, persistent metabolic activity was noted in the subcarinal mediastinal lymph nodes, prompting treatment with stereotactic body radiation therapy (SBRT), delivering a total dose of 35 Gy in five fractions in June 2023.
During chemotherapy in May 2023, brain imaging revealed further intracranial disease progression (Fig. 1C), necessitating additional SRS for the newly detected brain lesion.
The patient remained clinically stable until October 2023, when he presented with severe constipation. Colonoscopy revealed a large, proliferative mass at 75 cm from the anal verge, likely in the proximal transverse colon, occluding the lumen and preventing further scope advancement. Multiple biopsies were taken. The rest of the colon and retroflexion views were normal. Further evaluation identified an obstructing caecal mass, which, upon biopsy, was confirmed to be metastatic disease. PET imaging at that time revealed extensive hepatic metastases (Fig. 5). The malignancy exhibited rapid progression, culminating in hepatic failure within a few weeks, and the patient subsequently succumbed to the disease.

3
Discussion
We presented a case of metastatic pleomorphic carcinoma of the lung that was initially treated with immune checkpoint inhibitors (ICIs) and later with cytotoxic chemotherapy.
Microscopically, PGCC exhibits a heterogeneous architectural pattern with a predominance of bizarre, anaplastic cells that demonstrate marked nuclear pleomorphism, hyperchromasia, and abundant eosinophilic cytoplasm. The tumor cells are frequently multinucleated, with irregular nuclear contours, coarse chromatin, and prominent nucleoli. Mitotic activity is typically brisk, with numerous atypical mitotic figures, reflecting the high proliferative potential of the tumor [14,15]. Immunohistochemical (IHC) analysis is crucial for the diagnosis of PGCC, given its poorly differentiated morphology and overlapping features with other sarcomatoid and undifferentiated malignancies. The tumor typically exhibits co-expression of epithelial and mesenchymal markers, reflecting its biphasic differentiation potential [12,15,16]. Cytokeratins (CK5/6, CK7, CK AE1/AE3, CAM 5.2) are frequently positive, confirming epithelial differentiation. However, some cases may exhibit focal or weak expression. Napsin A and TTF-1 are variably expressed; positivity supports an adenocarcinomatous component. On the other hand, p40 and p63 positivity indicate squamous differentiation. [16,17]. Ki-67 typically demonstrates a high proliferative index (>50 %), indicative of aggressive biological behavior [[17], [18], [19]].
Managing pleomorphic carcinoma is particularly challenging due to its aggressive behavior and limited response to standard treatments. Unfortunately, there are no large-scale randomized controlled trials to establish the effectiveness and safety of ICIs—whether used alone or in combination with chemotherapy [20,21]. Surgical resection remains the primary treatment option for localized disease, offering the best chance for prolonged survival [22]. Even with surgery, data to support long term survival is scanty [22,23]. Nonetheless, many cases present at an advanced stage, precluding curative surgery, as in this case. In such instances, a combination of chemotherapy and immunotherapy therapy is employed, although the response rates are generally low [23].
According to the National Comprehensive Cancer Network (NCCN) [24] and the European Society for Medical Oncology (ESMO) [25], the treatment for metastatic NSCLC with PD-L1 expression generally involves the use of immune checkpoint inhibitors, which block the PD-1/PD-L1 axis and restore T-cell–mediated antitumor activity [24]. Therapeutic agents in this category include PD-1 inhibitors such as Pembrolizumab [25], Nivolumab, and Cemiplimab, as well as PD-L1 inhibitors such as Atezolizumab and Durvalumab. Selection of first-line immunotherapy is guided by the level of PD-L1 expression [24,25]. Notably, PGCC, a rare and aggressive NSCLC subtype, frequently demonstrates high PD-L1 expression and therefore is particularly amenable to treatment with immune checkpoint blockade. Accordingly, PD-L1 testing represents a critical step in the diagnostic and therapeutic planning for this tumor type [24].
Recent studies have highlighted the potential of ICIs in improving survival outcomes for patients with this challenging cancer type. For instance, a study reported cases where patients with PGCC treated with ICIs, such as Pembrolizumab, showed some tumor reduction, suggesting that these therapies may offer new hope in managing this aggressive disease [26]. Moreover, the expression of high levels of programmed death-ligand 1 (PD-L1) in PGCC tumors supports the rationale for utilizing ICIs, as it indicates a potential responsiveness to this form of immunotherapy [27]. Overall, while the evidence is still emerging, ICIs represent a promising avenue for enhancing treatment strategies for patients suffering from lung PGCC, particularly when incorporated into multimodal systemic anti-cancer treatments.
Targeted therapies through tyrosine kinase inhibitors, have shown promise in selected patients with specific molecular alterations [28], but response to treatment is usually limited and short-lived. For example, in a retrospective study of 16 patients with PGCC, by Taumura et al., eleven cases received combination chemotherapy as first-line but did not achieve an objective response, while one patient who treated with Docetaxel as second-line had partial response. The same study reported a durable response of nine years in one patient treated with cisplatin and gemcitabine. Another patient with EGFR exon 19 deletion received Gefitinib after postoperative relapse and attained a complete response of almost three years [29]. A real-world data analysis conducted by Chang et al. on 101 patients with metastatic lung spindle cell and/or giant cell carcinoma found that 44 patients (43.1 %) received platinum-based doublet chemotherapy, 27 patients (26.7 %) underwent targeted therapy, and 23 patients (22.8 %) were treated with ICI. The median overall survival (OS) for the cohort was 6.3 months [95 % confidence interval (CI): 3.6–9.0 months]. Among patients who received systemic therapy, those treated with ICIs achieved a longer median OS of 18.2 months compared to those who did not receive [30].
In our case, the patient was diagnosed with de novo metastatic disease, which unfortunately meant that curative treatment was not an option. Genetic testing of his biopsy did not identify any targetable mutations, ruling out the possibility of targeted therapy. As a result, he was initially treated with a combination of ICIs, Nivolumab and Ipilimumab, and completed four cycles. Encouragingly, a follow-up FDG PET scan demonstrated a partial response, leading to a transition to Nivolumab monotherapy. Unfortunately, the disease progressed shortly after the first cycle. In light of this, his treatment was promptly revised to include chemotherapy with the MAID regimen. After three cycles, a follow-up FDG PET scan indicated stable disease, leading to an extension of treatment with two additional cycles. This approach resulted in a progression-free survival (PFS) of six months—slightly longer than what has been previously reported in the literature, where the median PFS with MAID is about 2.8 months in patients with pleomorphic carcinoma.
Short-term survival is heavily influenced by the extent of disease at diagnosis, with localized cases having better outcomes due to curative treatment, especially surgery. Long-term survival remains elusive, with a 5-year survival rate of less than 10 % [31]. Factors associated with improved prognosis include early detection, complete surgical resection, and response to systemic therapies. Studies have reported five-year overall survival rates ranging from approximately 25.6 %–39.2 % following surgical intervention [32]. The curative rate in localised disease is heavily impacted by the involvement of local lymph node. For instance, patients without lymphatic metastasis (N0) have demonstrated five-year survival rates of about 32.5 %, whereas those with lymphatic involvement (N1-2) exhibit rates around 17.1 % [[31], [32], [33]]. Current literature reports a median survival of only 6–12 months for patients with metastatic disease, emphasizing the urgent need for novel therapeutic strategies and further research to improve survival and quality of life in this patient population [34,35]. Our patient survived for 30 months after his original diagnosis.
We believe our proactive approach in managing the brain metastasis with SRS and close of monitoring of the disease response through sequential FDG PET scan and subsequent change in the systemic anti-cancer treatment, improved his PFS and overall survival.
This case strongly emphasizes the pivotal contribution of multidisciplinary care in managing such aggressive malignancies, where the close collaboration of medical oncology, radiation oncology, radiology, and pathology teams enabled dynamic, evidence-based adjustments in treatment strategy. The use of sequential systemic therapies—transitioning from immunotherapy to multiple lines of chemotherapy—combined with targeted local interventions such as SRS and SBRT, exemplifies how coordinated, multimodal management can achieve meaningful disease control, symptom palliation, and survival extension even in advanced-stage PGCC.

4
Conclusion
Despite the aggressive nature and poor prognosis of pleomorphic giant cell carcinoma, our patient achieved an overall survival of 30 months, which exceeds the median survival typically reported for metastatic cases. This prolonged outcome likely reflects the benefits of a multimodal treatment strategy integrating immunotherapy, sequential chemotherapy, stereotactic radiotherapy, and continuous disease monitoring. The case highlights the vital role of a multidisciplinary team in adapting treatment plans to disease evolution, underscoring that individualized, coordinated care can meaningfully extend survival even in rare and treatment-resistant malignancies.

CRediT authorship contribution statement
Aladdin Kanbour: Writing – review & editing, Writing – original draft, Methodology, Data curation. Afnan Alnajjar: Writing – review & editing, Writing – original draft, Methodology, Data curation. Mohannad N. AbuHaweeleh: Writing – review & editing, Writing – original draft. Issam Al-Bozom: Writing – review & editing, Writing – original draft, Investigation. Bara Wazwaz: Writing – review & editing, Writing – original draft, Investigation. Athar Haroon: Writing – review & editing, Writing – original draft, Investigation. Razhan Madhar: Writing – review & editing. Harman Saman: Writing – review & editing, Writing – original draft, Supervision.

Consent
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

Ethical approval
This manuscript has been reviewed and approved by the Institutional Review Board (IRB) under approval number MRC-04-25-762, ensuring adherence to ethical guidelines and participant safety protocols.

Data availability statement
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Clinical trial number
Not applicable.

Financial disclosure
None of the authors has a financial interest in any of the products, devices, or drugs mentioned in this manuscript.

Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.