Occult Metastatic Non-Small Cell Lung Cancer Presenting as Sepsis with Multi-Organ Dysfunction: A Diagnostic Challenge, A Case Report

Abstract

Background: Sepsis is a critical illness arising from an infection, often accompanied by challenges in detection and treatment, particularly when the source of the infection is unknown or the patient’s condition progresses beyond expectations. Sometimes, clinically occult malignancies may either initiate or mimic sepsis, complicating diagnostic evaluation and management pathways.

Case presentation: A 67-year-old White Hispanic woman with no previously documented chronic medical conditions presented with bilateral lower-extremity swelling, progressive weakness, and worsening fatigue. Upon admission, she exhibited septic shock physiology with multi-organ dysfunction, including acute kidney injury, hyponatremia, and deep vein thrombosis, raising concern for severe infection or malignancy-associated systemic inflammatory response syndrome. Chest imaging demonstrated bilateral pulmonary infiltrates, pleural effusions, and a dominant pulmonary mass. Additional imaging revealed multiple hepatic lesions and a solitary brain metastasis. Despite initiation of broad-spectrum antimicrobial therapy, microbiologic cultures remained unrevealing, and the patient’s clinical condition progressively deteriorated. Histopathologic evaluation of a liver biopsy ultimately confirmed metastatic pulmonary adenocarcinoma consistent with non-small cell lung cancer (NSCLC). Due to continued clinical decline despite aggressive supportive management, multidisciplinary discussions were held, and care was transitioned to comfort-focused measures. The patient passed away one week after hospitalization.

Conclusion: This case highlights the challenges of maintaining an appropriate differential diagnosis in septic patients, especially when clinical findings are atypical or treatment responses are suboptimal. Optimizing outcomes and aligning management with patient goals requires early recognition of the underlying malignancy and timely involvement of palliative and specialty care teams.

Graphical abstract

Keywords

sepsis / multi-organ dysfunction syndrome (MODS) / metastatic cancer / non-small cell lung cancer (NSCLC)

Introduction

Sepsis is a global health crisis, accounting for nearly 11 million deaths each year, which translates to one in every five deaths worldwide[1]. It is described as life-threatening organ dysfunction due to a dysregulated host response to infection[2]. Even with advancements in diagnostic and therapeutic efforts, sepsis continues to present diagnostic uncertainty, especially when symptoms overlap with other systemic diseases, including malignancies[3]. Malignancy can predispose to sepsis and mimic sepsis, as the inflammatory cascade of cancer, necrosis, or cytokine interactions can manifest as systemic inflammatory response syndrome (SIRS), even in the absence of infection[4]. On the other hand, infection in patients with undiagnosed or metastatic cancer may present with sepsis of an unclear or mixed etiology, which muddies the diagnostic picture[5]. Among these, solid cancers, especially lung, gastrointestinal, and hepatobiliary cancers, are well documented as involving atypical presentations, such as unexplained fever, leukocytosis, or multiorgan dysfunction[6].

Older adults represent a unique diagnostic challenge due to age-related immune dysregulation, non-specific constitutional symptoms, and comorbidities that can obscure the etiological basis[7]. Additionally, malignancy-associated infections have often been found to have multifactorial origins, including infarction due to tumor necrosis, tumor vascular obstruction, suppression of immunity, or toxicity associated with treatment[8]. Given these complexities, clinicians should maintain a broad differential diagnosis in cases of persistent or atypical sepsis and consider early imaging and histopathologic evaluation[9].

This case demonstrates the significant diagnostic overlap among infection, malignancy, and systemic inflammatory response in critically ill patients. It emphasizes the necessity of early multidisciplinary collaboration to enhance recognition, prognostication, and alignment of care with patient goals. The rapid progression from initial presentation to multi-organ failure and subsequent transition to comfort-focused management, despite prompt medical evaluation, further highlights the aggressive clinical course that occult metastatic non-small cell lung cancer (NSCLC) may exhibit when presenting with sepsis-like physiology.

Case presentation

A 67-year-old White Hispanic female with no previously documented chronic medical conditions presented to the emergency department after approximately two weeks of progressive bilateral lower-extremity swelling, generalized weakness, and worsening fatigue. She denied preceding respiratory symptoms, trauma, recent hospitalizations, or known infections. On the day of presentation, she was found to be febrile (38.2°C), tachycardic (heart rate 120 bpm), and hypotensive (90/55 mmHg). Physical examination demonstrated bilateral pitting lower-extremity edema, proximal motor weakness (3/5 on the Medical Research Council scale), and mild confusion, raising concern for sepsis with early multi-organ dysfunction. Initial laboratory evaluation obtained on admission revealed leukocytosis (WBC 18,000/µL), elevated serum lactate (3.4 mmol/L), and acute kidney injury (creatinine 2.8 mg/dL). A comprehensive infectious evaluation was conducted during hospitalization. Blood, urine, and pleural fluid cultures remained negative. Sputum cultures did not identify a definitive pathogen. Procalcitonin levels were not obtained. C-reactive protein (CRP) and other inflammatory markers were elevated but were considered non-specific given advanced malignancy and systemic inflammation. Infectious disease specialists were consulted early because of concerns for severe sepsis versus a malignancy-associated inflammatory response. Broad-spectrum antimicrobial therapy was started empirically for hemodynamic instability and pulmonary infiltrates, but no infectious source requiring procedural intervention was identified.

According to the patient’s family, there was a history of chronic alcohol consumption; however, no formal diagnosis of cirrhosis or chronic alcohol-related liver disease had been established. The predominance of aspartate aminotransferase (AST) in her liver function tests suggested possible alcohol-related hepatic injury in the setting of metastatic disease.

Chest imaging was performed due to progressive respiratory compromise and systemic instability. Computed tomography (CT) of the chest (Figure 1) revealed a dominant right hilar and right upper lobe pulmonary mass, bilateral nodular pulmonary opacities, multifocal consolidative changes with air bronchograms, and bilateral pleural effusions, more pronounced on the left. Mediastinal and hilar lymphadenopathy were also present. No definite cavitary lesions were seen. These findings suggested advanced primary pulmonary malignancy with possible lymphangitic spread and post-obstructive pneumonia, rather than isolated infectious pneumonia. Chest radiography confirmed a persistent right mediastinal and lung mass with adjacent airspace disease and bilateral pleural effusions. Due to the patient’s hemodynamic instability, empiric ceftriaxone and azithromycin were started for presumed superimposed pneumonia while further diagnostic evaluation continued.

During the initial 48 h of hospitalization, persistent hemodynamic instability and worsening mental status prompted further diagnostic evaluation. A CT scan of the abdomen and pelvis (Figure 2) demonstrated hepatomegaly with multiple hepatic masses and ascites. Liver function tests showed marked increases in AST (212), ALT (57), and GGT (418). Several tumor markers were elevated, including CA19-9 (2217), CA125 (343), CA27.29 (260), and CEA (769). These results were interpreted with caution as non-specific indicators of a substantial systemic malignancy burden, rather than as diagnostic markers specific to NSCLC. The liver ultrasound confirmed multiple hypoechoic metastatic lesions. She had a chronic alcohol history, and the AST predominance in her liver function tests raised concern for alcohol-related hepatic damage in the context of cancer metastasis. Neurologically, she presented with mild confusion relative to her metabolic derangements. CT of her head (Figure 3) demonstrated a 3 cm temporal mass, and neurology and neurosurgery were consulted. Magnetic resonance imaging (MRI) of her brain was completed for further evaluation of the temporal lobe lesion seen on head CT (Figure 3). During the hospitalization, she developed right leg swelling. Doppler ultrasound showed right femoral deep vein thrombosis (DVT). A heparin drip was started, but due to the extent of her disease and concern for compromise to her respiratory status, an inferior vena cava (IVC) filter was placed for protection against emboli.

Her kidney function deteriorated even with robust IV fluid resuscitation; her creatinine level increased from 2.8 to 3.06 mg/dL, and she continued to develop oliguria. Nephrology was consulted, but ultimately, dialysis was not initiated due to both the patient’s hemodynamic instability and poor prognosis. With further management, she developed electrolyte derangements, specifically severe hyponatremia (Na⁺ 121 mEq/L) and hyperkalemia (K⁺ 5.5 mEq/L). She was treated with hypertonic saline and urea for hyponatremia, and Lokelma with calcium gluconate for hyperkalemia.

An additional workup revealed iron deficiency anemia (Hb 7.6 g/dL) that led to the transfusion of packed red blood cells (RBCs) and the initiation of proton pump inhibitor (PPI) therapy due to concern for an occult gastrointestinal (GI) bleed. At that point, the surgical consult was contacted again for further evaluation. Later in the hospitalization, she developed profuse diarrhea. Stool studies confirmed C. difficile colitis. Due to ongoing hemodynamic instability and worsening multi-organ dysfunction despite empiric antimicrobial therapy, antibiotic coverage was expanded. Concurrently, further diagnostic evaluation for occult malignancy and alternative etiologies was initiated (detailed antimicrobial regimens and laboratory trajectories are summarized in Table 1). Although intensive supportive care was administered, the patient’s condition continued to worsen.

Given the constellation of findings, alternative diagnoses were considered, including disseminated infection with septic emboli, primary hepatobiliary malignancy, lymphoma, and inflammatory or autoimmune processes. However, the presence of a dominant pulmonary mass, widespread hepatic lesions, markedly elevated carcinoma-associated tumor markers, brain metastasis, and cancer-associated thrombosis favored a diagnosis of metastatic solid malignancy. These considerations prompted further evaluation with a liver biopsy and serum cytokeratin fragment antigen 21-1 (CYFRA 21-1) level, selected due to its established association with NSCLC burden and prognostic value in advanced disease. Brain MRI was subsequently completed and confirmed a metastatic temporal lobe lesion without evidence of acute hemorrhage or mass effect requiring neurosurgical intervention.

Histopathologic evaluation of the liver biopsy demonstrated metastatic pulmonary adenocarcinoma consistent with NSCLC. Immunohistochemical staining was positive for TTF-1, CK7, and Napsin A and negative for p40, supporting a primary pulmonary adenocarcinoma origin.

Despite aggressive supportive care and escalation of antimicrobial therapy, the patient’s condition deteriorated progressively over the subsequent hospital days, with the development of worsening respiratory failure, septic shock, acute renal failure, and hepatic dysfunction.

The clinical timeline, summarized in relative hospital days and including symptom onset, key diagnostic steps, antimicrobial escalation, identification of metastatic malignancy, and clinical deterioration, is shown in Figure 4.

Discussion

Sepsis with multi-organ dysfunction syndrome (MODS) has been described in association with advanced malignancy, in which tumor burden, immune dysregulation, and cytokine-mediated inflammation may contribute to systemic inflammatory states that coexist with or mimic infection[10]. In this case, the initial clinical course was dominated by a septic shock phenotype, which delayed consideration of an underlying metastatic malignancy until imaging and biopsy clarified the etiology.

In this instance, the initial presentation with pneumonia and multi-organ dysfunction obscured the diagnosis of disseminated, previously unrecognized lung cancer. Lung cancer, especially NSCLC, is the leading cause of cancer-related deaths globally, with an estimated 2.2 million new cases and 1.8 million deaths each year[11]. Up to 40% of NSCLC present at an advanced or metastatic stage, with the liver, brain, adrenal glands, and bones commonly involved[12]. Within this clinical context, distinguishing infection-driven pathology from malignancy-associated systemic inflammation is particularly challenging when patients deteriorate despite appropriate sepsis-directed therapy. In retrospect, the radiographic findings of a central pulmonary mass, nodular disease, pleural effusions, and mediastinal involvement suggest advanced pulmonary malignancy. Post-obstructive and lymphangitic processes likely contributed to the patient’s respiratory decline.

The patient’s rapid deterioration highlights the complex overlap between true infection-related sepsis and malignancy-driven systemic inflammation. In this case, findings such as fever, leukocytosis, elevated lactate, and radiographic pneumonia were consistent with infectious sepsis. In contrast, features including extensive hepatic metastases, markedly elevated tumor markers, brain metastasis, and cancer-associated thrombosis were attributable to advanced malignancy. Recognition of these parallel processes is essential to avoid conflating etiologies and to guide appropriate diagnostic prioritization and prognostication[13]. Similar cases of occult malignancy initially presenting with sepsis-like physiology have been reported, especially in patients with advanced lung or gastrointestinal cancers. These cases often involve delayed oncologic recognition, negative or non-specific infectious workup, rapid progression to multiorgan dysfunction, and poor short-term prognosis despite broad-spectrum antimicrobial therapy. In contrast to previous reports, our patient experienced an unusually rapid clinical decline, necessitating a transition to comfort-focused care within days of diagnosis, despite early multidisciplinary evaluation[14]. The challenging aspect is that each requires early identification to enable appropriate management of its respective etiology. The patient’s presentation closely aligns with previously reported cohorts in which occult malignancy initially manifests as sepsis or septic shock prior to cancer diagnosis. Although this phenomenon is increasingly recognized in the literature, it remains diagnostically challenging because infection-related findings frequently dominate the initial clinical evaluation. In this case, the coexistence of pneumonia, leukocytosis, elevated lactate, and hemodynamic instability initially supported a sepsis-centered approach, while the underlying metastatic NSCLC remained clinically occult until advanced imaging and histopathologic evaluation were completed. This case, therefore, represents a clinically important and likely underrecognized subgroup of patients in whom malignancy-associated inflammation and true infection coexist, contributing to delayed oncologic recognition and poor outcomes[15].

This case demonstrates the considerable diagnostic overlap between infectious sepsis and malignancy-associated SIRS or MODS in patients with advanced cancer. Although the patient exhibited profound leukocytosis, elevated lactate, hypotension, respiratory failure, and radiographic pulmonary abnormalities consistent with sepsis, comprehensive microbiologic evaluation, including blood, urine, and pleural fluid cultures, yielded negative results. The lack of an identifiable infectious source suggests that malignancy-driven systemic inflammation may have contributed substantially to the patient’s clinical deterioration, rather than infection alone. Advanced metastatic NSCLC can induce a severe proinflammatory state through cytokine dysregulation, tumor necrosis, and immune activation, resulting in clinical features that closely mimic septic shock. This diagnostic ambiguity underscores the necessity of considering occult malignancy in patients who present with apparent sepsis but lack microbiologic confirmation[16].

Recent literature has increasingly recognized the diagnostic overlap between infectious sepsis and malignancy-associated systemic inflammatory syndromes in patients with advanced cancer. Shared clinical features include hemodynamic instability, elevated inflammatory markers, negative or non-specific microbiologic findings, delayed oncologic diagnosis, and rapid progression to multiorgan dysfunction despite antimicrobial therapy[17–20].

This case highlights a critical clinical consideration: patients presenting with presumed sepsis who exhibit atypical imaging findings, disproportionate tumor marker elevation, thrombotic complications, or persistent clinical deterioration despite appropriate antimicrobial therapy should undergo early evaluation for occult malignancy. In this instance, the coexistence of pulmonary mass lesions, hepatic metastases, brain involvement, and cancer-associated thrombosis ultimately established the diagnosis of metastatic NSCLC presenting with sepsis-like physiology. As summarized in Table 2, previously reported cases describing occult malignancy presenting with sepsis-like physiology share several overlapping clinical characteristics, including non-specific infectious findings, delayed oncologic recognition, rapid progression to multiorgan dysfunction, and poor short-term outcomes despite broad-spectrum antimicrobial therapy[17–20].

The presence of hepatic metastasis, as observed in this patient, is a common site of involvement in NSCLC and is often associated with cholestatic liver injury, coagulopathy, and ascites[21]. Liver metastasis can exacerbate systemic inflammation and impair endotoxin detoxification, thereby increasing the severity of sepsis[22]. Also, brain metastases from lung cancer occur in approximately 30%–40% of patients at some point during the course of their illness and can be seen with minimal neurological deficits or confusion—symptoms that can be easily misattributed to metabolic encephalopathy or septic delirium[23].

The observed hypercoagulable state, evidenced by the patient’s deep venous thrombosis, aligns with Trousseau syndrome, a malignancy-associated thrombotic phenomenon typically linked to mucin-producing adenocarcinomas, such as pulmonary adenocarcinoma[24]. The liver biopsy immunophenotype confirming metastatic pulmonary adenocarcinoma further substantiates this interpretation.

Cancer-associated thrombosis represents a significant cause of morbidity and mortality in cancer patients, and it can develop months before the diagnosis of cancer[25]. The concurrent diagnosis of C. difficile colitis is evidence of profound immunologic compromise in the patient—most likely multifactorial, stemming from systemic inflammation, broad-spectrum antibiotic therapy, and malignancy-induced immune dysfunction[26].

This case highlights the diagnostic challenges that occur when infection and malignancy overlap. Clinicians should evaluate alternative non-infectious etiologies, such as malignancy, autoimmune disease, or endocrine disorders, if the clinical course does not align with the anticipated response to antimicrobial therapy or if diagnostic findings remain atypical despite continued treatment[27]. Certain infectious pathogens and opportunistic infections often exhibit delayed microbiologic identification or slower therapeutic response, which complicates diagnostic assessment in critically ill patients.

Advanced imaging (for example, contrast-enhanced CT, MRI) and tissue biopsy, when applicable, are the gold standard for differentiating infection from malignancy or malignant infiltration[28].

Involvement of multidisciplinary teams, including oncology, infectious disease, and palliative care, early on in complex cases is also essential[29]. Early oncologic recognition not only sets the stage for appropriate therapy but also begins a conversation about goals of care and ensures that management is congruent with patient values and quality of life[30]. At a broader institutional level, this case illustrates the need for protocols for patients presenting with “sepsis of unknown origin”, including parallel malignancy screening when the clinical course or laboratory data are inconsistent with typical infectious courses. Such protocols may allow for earlier cancer detection and optimize the transition from curative to palliative intent.

While broad tumor marker panels can sometimes raise suspicion for underlying malignancy in complex cases, many markers, including CA19-9, CA125, and CA27.29, are non-specific and should not be regarded as diagnostic for NSCLC. In contrast, markers such as carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA 21-1) demonstrate greater clinical relevance in advanced NSCLC and may offer supportive prognostic or disease-burden information when evaluated within the broader clinical and radiographic context[31]. The diagnosis of metastatic NSCLC in this patient was confirmed based on histopathologic and immunohistochemical evaluation, rather than solely on serum tumor marker elevation.

This case highlights the importance of reassessing the differential diagnosis in septic patients who fail to improve as expected, with early consideration of underlying malignancy when clinical, laboratory, or imaging findings are atypical.

Conclusion

This case highlights the urgent need to maintain a broad differential diagnosis for septic patients, especially when the usual treatments are not yielding expected results or when unexpected findings arise. Prompt evaluation for underlying malignancies is recommended, particularly in individuals with a substantial smoking history or clinical features suggestive of occult cancer. Getting the right specialists involved promptly and discussing care goals are crucial for guiding treatment and ensuring it aligns with the patient’s values. Earlier recognition of disproportionate hepatic involvement, markedly elevated tumor markers, and cancer-associated thrombosis may represent potential diagnostic triggers warranting earlier oncologic evaluation in similar presentations.

Key learning points: Sepsis can be the first indication of a hidden cancerous growth. When this occurs, the patient’s condition often continues to decline significantly after the sepsis has been treated.

• If a patient’s condition does not improve within 48–72 h after starting antibiotics, it is essential to look for other possible reasons for the patient’s illness, including the possibility that the patient has cancer.

• Both infections and cancers may occur, and an appropriate differential diagnosis of both conditions is necessary to develop accurate prognostic information and determine the best treatment options.

• Timely involvement of a multidisciplinary team promotes prompt diagnosis and accurate prognosis and can align treatment with the needs of the patient.

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