Pleomorphic carcinoma of the lung with paraneoplastic fever as presentation

Abstract

Pulmonary pleomorphic carcinoma (PPC) is a rare, highly aggressive variant of non-small cell lung cancer (NSCLC), comprising 0.1–0.4% of all pulmonary malignancies. While lung cancers typically present with symptoms like cough and hemoptysis, paraneoplastic syndromes are observed in about 10% of cases. Paraneoplastic fever as an initial manifestation is extremely rare. We present a rare case of PPC with neoplastic fever, emphasizing the importance of paraneoplastic syndromes during the evaluation of lung cancer. Surgical resection successfully alleviates neoplastic fever, highlighting the need to recognize paraneoplastic fever as a diagnostic challenge and consider it as a differential in cases of unexplained fever for prompt intervention.

Introduction

Pulmonary pleomorphic carcinoma (PPC) is a rare, highly invasive, biphasic type of pulmonary cancer that combines spindle or giant cell carcinoma with any of the more common types of non-small cell lung cancer (NSCLC). It is usually aggressive in nature, with extensive metastases at presentation in majority of the cases and thus carries a very poor prognosis [1]. The incidence of PPC ranges from 0.1 to 0.4% of all pulmonary malignancies [2]. Cough and hemoptysis are the most commonly reported symptoms [2]. Paraneoplastic syndromes (PNS) occur in approximately 10% of lung cancer patients [3]. The two most common presentations of PNS include humoral hypercalcemia of malignancy in squamous cell carcinoma and syndrome of inappropriate antidiuretic hormone secretion in small cell lung cancer. Although the true incidence is not known, PPC rarely presents as paraneoplastic fever. It is a rare entity attributed to the cytokine-mediated effect of malignancy and is a diagnosis of exclusion, making it difficult to diagnose. The common causes of fever associated with malignancy include infection, neutropenia, transfusion, thrombosis, and drug reactions. Once all these causes are ruled out, then only a possibility of neoplastic fever should be considered [4]. It represents critical clinical phenomena that may precede or overshadow tumor diagnosis, as observed in our case. Awareness and recognition of these manifestations are essential for timely diagnosis and management.

We herein report a case of pleomorphic carcinoma of the lung presenting with paraneoplastic fever where surgical resection alleviated the PNS.

Case report

A 58-year-old gentleman, a chronic smoker, presented with a complaint of recurrent episodes of fever for the past 3 months. Fever was not associated with chills or rigors, and it was not relieved with medications. The patient has been seropositive for hepatitis B for 6 months, and he was on regular medications for the same with normal liver function tests and undetectable hepatitis B virus deoxyribonucleic acid (HBV DNA). The patient had multiple prior visits to physicians for the fever, but no infective focus could be delineated. Basic hematological investigations, including total leucocyte count and cultures of blood, urine, and sputum, were reported to be normal. The patient continued to have a persistent daily fever of > 38 °C. Serum procalcitonin was also within normal range. The patient was initially evaluated at an outside hospital and had received multiple courses of oral antibiotics from different practitioners.

A contrast-enhanced computed tomography (CECT) chest demonstrated a 6 × 4 cm well-defined mass-like consolidation without an air bronchogram in the posterior basal segment of the right lower lobe with sub-centimetric mediastinal lymphadenopathy (Fig. 1a). Bronchoscopy revealed an inflamed posterior commissural wall attributed to gastroesophageal reflux disease (GERD). Thick secretions with abnormal mucosa in the posterior segment of the right lower lobe indicated an infectious cause. Lavage analysis showed no acid-fast bacilli (AFB), fungi, or pathogens. Additional tests were all negative for malignancy, Mycobacterium tuberculosis (MTB), and pneumonia panel results.

Fig. 1.

a Axial CECT image depicting a well-defined 6 × 4 cm mass-like consolidation (red arrow) in the posterior basal segment of the right lower lobe with b infiltration into the underlying diaphragm (diaphragm indicated by red arrow). c Whole-body PET-CT axial image demonstrating fluorodeoxyglucose (FDG) avidity of the mass (red arrow)

Whole-body positron emission tomography-computed tomography (PET-CT) performed one and a half months later revealed a mass lesion of 8.1 × 5.2 cm with a maximum standardized uptake value (SUVmax) of 15.3 in the posterior and medial basal segment of the right lung lower lobe infiltrating the underlying diaphragm (Fig. 1b, c). Scans were reviewed at our center, and considering strong radiological suspicion of a malignant lung mass, a computed tomography-guided (CT-guided) biopsy was done. In the meantime, his fever was managed with injectable antibiotics under the guidance of an infectious disease expert and pulmonologist at our center, and a complete workup was done to rule out other common causes of fever, including anti-cyclic citrullinated peptide (anti-CCP) antibodies, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). The whole workup did not reveal any abnormality, but the fever was not relieved despite higher generation of antibiotics and antipyretics. The biopsy report revealed it to be a poorly differentiated carcinoma with immunohistochemistry (IHC) diffusely positive for cytokeratin (CK), Brahma‐Related Gene‐1 (BRG-1) immune-expression retained and negative for thyroid transcription factor-1 (TTF1), P40, Nuclear protein in testis (NUT), Wilms’ tumor 1 (WT1), CLAUDIN4, GATA3, BEREP4, D240, and CALRETININ (Fig. 2a–d), and thus a possibility of paraneoplastic fever was taken into consideration. Contrast-enhanced magnetic resonance imaging (CE MRI) brain and endobronchial ultrasound (EBUS) mediastinal staging were reported to be normal.

Fig. 2.

Needle biopsy showing a lung parenchyma extensively infiltrated by poorly differentiated malignancy. b Tumor cells are polygonal exhibiting high-grade atypia with brisk mitosis (red arrow). Tumor cells are intricately admixed with inflammatory cells. c Tumor cells diffusely positive for CK. d BRG1 immunoexpression is retained in tumor cells (H&E, hematoxylin and eosin; DAB, diaminobenzidine)

In view of the likely paraneoplastic etiology of the fever and after having a multidisciplinary team discussion, a decision was taken to proceed with surgery. The patient underwent right video-assisted thoracoscopic surgery (VATS) involving right lower lobectomy with excision of a part of the right hemidiaphragm with primary repair of defect along with mediastinal lymph node dissection. His postoperative period was uneventful, and there were no further fever episodes, suggesting the paraneoplastic nature of the fever. Subsequently, his pathology findings demonstrated diffuse sheets of tumor cells with pleomorphic vesicular nuclei with an area of spindle cells along with giant cells comprising approximately 15% of the tumor area. Mitosis was brisk with atypical mitosis (Fig. 3a, b). All lymph nodes and margins were reported to be free. Collectively, the findings of pathology and immunostaining confirmed it to be a pleomorphic carcinoma and a final stage of pT4 N0, Stage IIIA was made. Molecular testing showed no targetable mutation, and programmed death-ligand 1 (PD-L1) was more than 50%. A repeat multidisciplinary team discussion was done, and he received four cycles of paclitaxel and cisplatin followed by 18 doses of pembrolizumab. The patient was disease-free at the last 6-month follow-up. There was no further episode of fever during follow-up.

Fig. 3.

Resection specimen revealed a moderately differentiated adenocarcinoma (red arrow) juxtaposed with undifferentiated carcinoma (right side). b Tumor cells were negative for TTF1 in both differentiated (left side with arrow) and undifferentiated areas

Discussion

PPC is a rare subtype of lung cancer, commonly linked to heavy smoking—a risk factor absent in our patient. The complexity of this case was further heightened by its initial presentation as paraneoplastic fever. Neoplastic fever should be considered in cancer patients presenting with pyrexia of unknown origin. While more common in hematological malignancies, it can occur with any cancer type and is a diagnosis of exclusion. The precise mechanism remains unclear but is thought to be driven by inflammatory cytokines such as interleukin-1 (IL-1), IL-6, tumor necrosis factor-alpha (TNF-α), and interferon, produced either by tumor cells or the host response [5]. Tumor necrosis can further release these cytokines, leading to prostaglandin E2 production and elevation of the hypothalamic temperature set point [5]. Differentiating between infectious and paraneoplastic fever is crucial because their management differs substantially and affects outcomes. If infection is suspected, surgery is generally postponed until the patient is stabilized.

In a retrospective study by Ito et al., three of 22 pleomorphic carcinoma patients presented with fever, although its paraneoplastic origin was not confirmed [2]. Neoplastic fever can mask the underlying tumor, potentially delaying accurate diagnosis and timely management.

Furthermore, Chen et al. [6] demonstrated that surgery served as an independent protective factor in PPC, reducing the risk of death by 88% in localized cases and 65% in regional cases. Therefore, even without prior knowledge of this specific histology, proceeding with upfront surgical resection in resectable lung cancer cases is critical—even if it requires extended resections. This was exemplified in our case, where the diaphragm was removed en-bloc with the mass, highlighting the importance of aggressive surgical intervention for improved outcomes.

According to the current World Health Organization (WHO) criteria [7], the diagnosis of sarcomatoid carcinoma is based solely on morphology without requiring immunohistochemistry. This contrasts with the classification of conventional NSCLC, where markers like TTF-1 and p40 are recommended. Additionally, due to pleomorphic differentiation and atypical cell morphology, a definitive diagnosis of pleomorphic carcinoma is often possible only in surgical specimens rather than biopsy samples, given the limited tissue availability [7]. In our case report, we conducted a comprehensive analysis that included both immunohistochemistry and molecular studies. This thorough approach enabled us to offer the patient a complete range of treatment options, as supported by findings from Weissferdt et al. [8].

PPC is known for its poor response to cytotoxic chemotherapy and worse prognosis compared to other NSCLC types, even with early diagnosis and resection [2]. In recent years, the emergence of novel targeted therapies and PD-L1 inhibitors has provided new treatment avenues for this histologic group, particularly given its high rate of systemic failure. Several case reports have identified epidermal growth factor receptor (EGFR) or Kirsten rat sarcoma virus (KRAS) gene mutations in PPC patients, with some showing promising outcomes from targeted therapy [9]. Moreover, retrospective analyses by Lee et al. [10] revealed that over 90% of PPC cases are PD-L1 positive, with higher tumor PD-L1 expression correlating with longer survival after initiating immune checkpoint inhibitors. Although PD-L1 may serve as a favorable biomarker for treatment efficacy, responses vary, suggesting other predictive factors may also be involved. Based on these insights, our patient was treated with pembrolizumab and remains disease-free at the latest follow-up.

Thus, surgeons should not hesitate to perform extended resections for this subtype, if necessary to achieve R0 (no residual tumor) resection for resectable cases, and one should perform molecular and PD-L1 testing similar to other types of NSCLC.

Conclusion

PPC can present as paraneoplastic fever, making it an important differential diagnosis in lung cancer cases, when other causes are excluded. Early recognition and surgical resection play a vital role in improving survival in localized cases. Given PPC’s high risk of systemic progression, routine molecular and PD-L1 testing is essential. A comprehensive approach that integrates surgery, molecular profiling, and immunotherapy is critical for optimizing outcomes in this rare and aggressive lung cancer subtype.

Author contribution

NKK performed the initial manuscript write-up, data collection, literature review, and manuscript editing. LMD and SP assisted with the literature review and editing of the manuscript.

Funding

None.

Data availability

The data supporting the findings of this case report are available from the corresponding author upon reasonable request.

Declarations

Human ethics and consent to participate

No formal ethical approval was required from the institutional ethical committee for this single-case report. Written informed consent was obtained from the patient for participation and publication. All patient data have been de-identified to ensure confidentiality in accordance with relevant guidelines and regulations.

Consent for publication

Written informed consent was obtained from the patient(s) for the publication of case details and accompanying images in a scientific journal.

Clinical trial number

N/A.

Competing interests

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.