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Primary gallbladder cancer (GBC) is a rare but lethal malignancy, constituting 1.2% of all cancers worldwide and 1.7% of cancer-related deaths [,]. Most GBCs progress silently and often present at a late stage, with a mean survival rate of 6 months and a 5-year survival rate of 5% [,]. As such, early diagnosis is crucial to improve mortality and morbidity []. GBC has a rather non-specific clinical presentation, showing vague symptoms such as anorexia and weight loss, as a precursor to jaundice, which would happen at a late stage with hepatic invasion or biliary tree compression from nodal metastasis.

GBC has significant geographic and demographic variation in its epidemiology. The highest incidence rates are reported in parts of Asia and South America, particularly in Chile, India, and China, whereas Western countries, such as the United States and most of Europe, exhibit a lower prevalence []. The disease is more common in women, with a female-to-male ratio of approximately 3:1, and is typically diagnosed in individuals over the age of 60 []. Several risk factors are strongly associated with GBC, including chronic gallstone disease, which is present in up to 80% of cases, and porcelain gallbladder, a condition characterized by calcification of the gallbladder wall. Other conditions linked to GBC include chronic inflammation due to infections such as Salmonella typhi, obesity, and primary sclerosing cholangitis. Additionally, genetic predispositions and environmental exposures, such as the high consumption of processed foods and industrial carcinogens, have been implicated in disease development [].

On rare occasions, GBC can be associated with paraneoplastic syndromes (PNSs)—most commonly dermatomyositis, leukocytosis, neurological syndromes and metabolic disturbances such as hypercalcaemia and hyponatremia []. While these syndromes are linked to cancer, the exact reason why they occur is not fully understood. Often, these symptoms are mistaken for other illnesses until the cancer is discovered, sometimes at a late or advanced stage. Physicians must be vigilant regarding the telltale signs of PNS and consider GBC in their diagnostic differentials. This systematic review offers a detailed exploration of the PNS linked to primary GBC and their impact on the diagnosis, management, and clinical outcomes.

A previous narrative review has already been conducted by Ali et al. [] on the spectrum of paraneoplastic syndromes associated with gallbladder carcinoma. However, in the study, Ali only focused on PNS linked with gallbladder carcinoma and not gallbladder cancer in general. The pathophysiology of the PNS was not addressed, and there was also no mention of the relevant investigations linked to the respective PNS or management strategies adopted to address the symptoms. Two previous literature reviews were conducted by Tohyama et al. [] and Wataru Izumo et al. [], which explored the extent of leukocytosis as a paraneoplastic syndrome in gallbladder cancers. However, both of these studies only focused on leukocytosis as the sole paraneoplastic syndrome. The link between leukocytosis and granulocyte-colony stimulating factor is also not further explored or searched for. This study bridges that problem by accounting for and explaining the relationship between the two. This study also adopts a systematic procedure by employing a more robust search strategy as well as assessing the risk of bias in the studies used.

This systematic review is the first to comprehensively evaluate the spectrum of PNSs in GBC, bridging key knowledge gaps in their pathophysiology, diagnosis, and clinical impact. Unlike prior reviews that focused on isolated manifestations, this study systematically categorises PNSs into haematological, dermatological, neurological, metabolic, and other subtypes, providing a broader and more detailed perspective. By employing a rigorous search strategy and assessing the risk of bias in included studies, this article strengthens the understanding of PNSs as potential diagnostic clues and prognostic indicators in GBC. Given the aggressive nature and late-stage detection of GBC, recognizing PNS could facilitate earlier diagnosis and optimize patient management. This study underscores the importance of heightened clinical vigilance for PNSs in GBC and lays the groundwork for future research on their pathophysiological mechanisms and therapeutic implications.

This study focused on adult patients (≥18 years old) with a confirmed diagnosis of GBC using imaging. The primary interest is in patients presenting with PNS, meaning those exhibiting symptoms not typically observed in the majority of GBC patients. To explore this unique patient population, a variety of study types, including case reports, case studies, clinical trials, and randomised controlled trials were analysed. PNS was defined as a systemic clinical manifestation of a malignancy causing an altered immune system [].

The criteria for exclusion included studies reporting on patients below 18 years of age, letters (of any form, including letters to editors), non-English studies, editorials, animal studies, and cancers that were deemed to be non-primary GBC.

A comprehensive literature search was conducted in five medical databases (PubMed, Embase, CINAHL, Web of Science, and Cochrane Library) up to April 2024, utilising MeSH terms and keywords. The search aimed to identify common patterns of PNS associated with GBC. Commonly reported symptoms included leukocytosis (often associated with elevated G-CSF (granulocyte colony-stimulating factor) levels), dermatomyositis, hyponatremia, and hypercalcaemia. These symptoms were incorporated into the search strategy following an initial broad search using “paraneoplastic” as a key phrase. Due to the limited research on this specific subject, the majority of studies identified were case studies. No case series or systematic reviews were found. Consequently, a forest plot and meta-analysis were not feasible.

The search results were exported and collated using the EndNote library. Duplicate records were removed using the software’s duplicate removal function. The remaining 1022 articles were then imported into Covidence, a systematic review management software, for manual screening. Two review authors independently screened the records using a dual-author, double-blinded method, reviewing titles and abstracts based on pre-defined inclusion and exclusion criteria. Covidence was employed as the screening platform. The University of Oxford Centre for Evidence-Based Medicine’s criteria were used to critically appraise the shortlisted references and determine their reliability and applicability. The full text of potentially eligible references was then retrieved and independently assessed by two review authors, with the assistance of a third review author to resolve any disagreements or uncertainties. The reasons for excluding ineligible studies were meticulously documented. Following the initial duplicate removal process, a total of 1022 papers remained. These were sourced from various databases: 397 from PubMed, 29 from Cochrane, 377 from Embase, 10 from CINAHL, and 209 from Web of Science.

Data from each included article were systematically extracted and compiled using a standardised template and then organised into a table format within Microsoft Excel. The data table included the article information (first author, year published, study design, article title, country), patient characteristics (overall sample size, study population, male:female ratio, mean/median age, GBC confirmatory diagnosis method, GBC type, presenting symptom, other highlighted comorbidities), PNS features (timing of PNS diagnosis, characteristics of gallbladder tumour, main PNS, associated symptoms), risk of study bias (this field documented the assessed risk of bias using a standardised tool), and study outcomes including metabolic (serum sodium, serum osmolality, urine osmolality, urine sodium, corrected calcium), dermatologic (erythrocyte sedimentation rate, leukocyte count), and hematologic (highest reported white blood cell count, laboratory G-CSF count). Any additional tests, management strategies, and survival time were reported.

The risk of bias in the included articles was assessed using the criteria specified in the Joanna Briggs Critical Appraisal Tool for Case Reports []. This included an assessment of the following: A clear description of the patient’s demographic and clinical characteristics (e.g., age, gender, medical history, etc.); Detailed description of the patient’s condition or diagnosis; Intervention or treatment provided and any changes made during the course of treatment; Clinical outcomes (improvement, complications, or other changes following the intervention); Follow-up and the duration of observation post-intervention; Whether there were any adverse events anticipated or identified; Discussion of why the case was unique or significant; Clear conclusions drawn from the case, including implications for future clinical practice or research. Each study was assessed with a score out of 8. Studies with lower scores implied the presence of bias in them. Two review authors independently used the criteria above to assess bias and resolved any differences by discussion with a third reviewer. Biasedness was summarised along with the characteristics of the included studies, which can be seen from the tables below.

A total of 49 studies were included in the manuscript. The majority of the studies included were case reports. The outcomes extracted were as follows. Development of any PNS post diagnosis of GBC; Type of treatments for GBC and PNS and its response. Investigation findings used to determine the presence of PNS; Signs or symptoms associated with the PNS. The study extraction process is described in our PRISMA-P chart, as shown in .

Leukocytosis, defined as a white blood cell count above 11,000/µL [], is a common PNS. In a review of GBC cases, leukocytosis was present in 34% of the cases, commonly attributed to tumour necrosis and inflammatory cytokine production [,]. It affects about 20% of solid tumour patients [], with G-CSF found to be the most implicated cytokine []. G-CSF promotes myeloid progenitor proliferation, leading to neutrophilia and a pro-inflammatory state via IL-1, IL-6, and TNF-α []. Tumour-derived G-CSF was further found to be linked to angiogenesis, metastasis, and systemic inflammatory signs such as low-grade fever.

Leukocytosis in gallbladder cancer (GBC) can arise from three main sources: (1) paraneoplastic leukocytosis (PL), (2) metastatic leukocytosis, and (3) infection-related leukocytosis. Paraneoplastic leukocytosis is characterised by extreme leukocytosis without bone marrow infiltration. It is primarily cytokine-driven, with G-CSF and IL-6 being the main contributors. Other causes of leukocytosis, such as metastatic leukocytosis, typically present with a moderate WBC elevation (12,000–20,000/μL) and bone marrow abnormalities [], while infectious leukocytosis, such as in cholangitis, is accompanied by fever, positive blood cultures, and typically resolves with antibiotic treatment, unlike PL. Persistent elevation of WBC count without evidence of infection suggests PL, while bone marrow examination can be considered to help differentiate PL from metastatic involvement. Among the reviewed studies, PL was the most likely form of leukocytosis observed in GBC.

Fifteen studies met the inclusion criteria, comprising 15 patients (8 females, 7 males) with a mean age of 60.1 years (range: 40–79). The results of the studies is summarised in . The mean leukocyte count was 42,000/µL (range: 12,600–132,000/µL). Five patients had extreme leukocytosis (>50,000/µL), meeting the criteria for Paraneoplastic Leukemoid Reaction (PLR), a severe form of leukocytosis linked to aggressive tumour biology. A total of 11 out of 15 patients also presented with a concurrent increase in serum G-CSF levels. The average G-CSF value was 286.9 pg/mL (range: 54–800), above the average G-CSF levels (<30 pg/mL) found in healthy individuals []. The first case of G-CSF linked to malignancy was reported by Asano []. To objectively classify G-CSF-producing cancer, Asano proposed four diagnostic criteria: (a) leukocytosis linked to malignancy that cannot be better explained by other causes, (b) elevated serum G-CSF levels, (c) a decrease in leukocyte and serum G-CSF count post tumour resection, and finally, and (d) immunohistological confirmation of G-CSF production within the tumour. Fulfilment of any single criterion strongly suggests that the cancer is G-CSF-producing. It should be noted that the sensitivity of criterion (d) is not high, with studies indicating it was only approximately 70% sensitive [,]. Using criteria (a)–(c), all 11 patients with elevated G-CSF levels can be assumed to be very likely to have a G-CSF-producing GBC.

The aetiology of the nonspecific abdominal pain may be attributed to chronic cholecystitis or gallbladder wall thickening []. Interestingly, some patients with confirmed GBC also displayed concomitant cholecystitis on CT scans. While the precise correlation between cholecystitis and GBC remains unclear, a proposed mechanism involves recurrent acute cholecystitis, leading to the release of pro-inflammatory cytokines such as IL-1, IL-6, and tumour necrosis factor-alpha (TNF-α). These cytokines may create a conducive environment for cancer development [], as seen in . Additionally, chronic mucosal inflammation associated with longstanding gallstones is considered a risk factor for carcinogenesis. Due to nonspecific symptoms, the majority of GBCs were discovered at a locally advanced stage []. This, coupled with severe leukocytosis and PLR, often leads to diagnostic confusion between infection and underlying cancer.

GBC diagnosis typically follows a two-step process: abdominal ultrasound or contrast-enhanced CT scan [,,]. Liver function tests and inflammatory markers will provide additional clues, though jaundice is a late sign, and inflammatory markers are noted to be inconsistently elevated. Approximately two-thirds of cases showed transaminitis, and one-third had inflammatory marker elevation. Tumour markers, such as CA19-9, were rarely elevated. Metastases to the liver and spine were found in nearly half of the patients. Interestingly, it was noted, from our review, that leukocytosis severity did not necessarily correlate with tumour burden, which suggests that there might be underlying factors contributing to leukocytosis that have yet to be discovered. Radical cholecystectomy remains the primary treatment [], often leading to reduced WBC counts and G-CSF levels. Chemotherapy and immunotherapy show variable success [,].

Paraneoplastic Leukemoid Reaction (PLR) is an extreme form of leukocytosis (>50,000/µL) in the absence of hematologic malignancy, often misdiagnosed as infection due to its presentation with fever, weight loss, and fatigue []. Unlike standard leukocytosis, PLR is driven by excessive tumour-derived cytokine secretion, predominantly granulocyte-colony stimulating factor (G-CSF) and interleukin-6 (IL-6), which promote neutrophil proliferation and a systemic inflammatory state []. This pro-inflammatory microenvironment contributes to tumour progression, angiogenesis, and immune evasion. PLR was most commonly seen in aggressive, high-burden malignancies, including lung, renal, and gastrointestinal cancers, with GBC representing a rarer but significant subset.

Peripheral blood smears in PLR typically revealed granulocytosis without immature blasts, differentiating it from leukaemia. Bone marrow biopsy findings are often normal or show reactive hyperplasia without dysplasia, further distinguishing PLR from primary hematologic disorders. Importantly, PLR is associated with poor prognosis, often correlating with advanced disease, high metastatic burden, and reduced survival. Among the included cases, PLR was exclusively observed in metastatic GBC, reinforcing its role as a marker of tumour aggressiveness. Management of PLR remains largely supportive, with leukapheresis considered in extreme cases. Corticosteroids and NSAIDs have been explored for symptomatic relief, though definitive management requires tumour-directed therapy, which has been shown to reduce leukocyte counts post-treatment []. Platinum-based regimens, particularly gemcitabine–cisplatin, have demonstrated efficacy in controlling both tumour progression and cytokine-driven leukocytosis in GBC. However, no standardised approach exists for PLR management, and further research is needed to determine whether it could serve as an early biomarker for aggressive tumour behaviour.

Inflammatory myositis, encompassing dermatomyositis and polymyositis, is an inflammatory myopathy characterised by proximal muscle weakness []. The initial association between inflammatory myositis and malignancy was first noted over a century ago []; however, it remains a relatively uncommon occurrence, affecting a significant minority of cancer patients. While paraneoplastic processes are understood to be linked to oncogenesis and autoimmunity, the precise pathophysiological mechanisms underlying paraneoplastic inflammatory myositis remain elusive []. The detection of myositis-specific antibodies provides evidence for this association []. Casciola-Rosen et al. proposed a mechanism where myositis autoantigens, expressed in regenerating muscle cells, share similarities with those found on tumour cells []. This suggests that an anticancer immune response targeting tumour cells could inadvertently cause muscle damage. Other proposed mechanisms include the involvement of humoral and cell-mediated immune responses and the presence of tumour antigens eliciting an autoimmune reaction []. Additionally, the secretion of hormones such as adrenocorticotropic hormone, growth hormone, and serotonin has been implicated as a potential pathogenic factor []. A schematic representation of these proposed pathophysiological mechanisms is depicted in .

Dermatomyositis presents characteristically with symmetrical proximal muscle weakness and a variety of dermatological manifestations, including a heliotrope rash and Gottron’s papules []. Other associated features may include eyelid oedema, pitting oedema, dysphagia, nasal regurgitation or aspiration pneumonia, and dyspnea. Notably, dermatological findings may be the sole manifestation in up to 40% of patients []. The pathophysiology of dermatomyositis classically involves the binding of immune complexes to endothelial cells. This triggers the complement system via the membrane-attack complex, leading to cell lysis and endothelial cell necrosis. The resulting impaired blood supply likely contributes to perifascicular atrophy. However, recent research suggests that a type I interferon-mediated cascade may be the predominant underlying mechanism []. Polymyositis presents with proximal muscle weakness, usually most severely in the pelvic girdle and shoulders [], and commonly in the neck flexors []. This is accompanied by a marked elevation of creatinine kinase. Its pathogenesis is characterised by local activation of immune cells in skeletal muscle. This is due to the expression of cytokines such as IFN-γ, IL-6, IL-1β, TNF-α, and TGF-β [] and chemokines like IL-8, CCL-2, CCL-3, CCL-4, CCL-5, CXCL-9, and CXCL-10 [].

This review analysed nine case reports, encompassing seven females and two males with a mean age of 67.7 years (range: 48–90 years), who presented with dermatomyositis as the primary PNS. summarises the timing of dermatomyositis diagnosis in relation to GBC, clinical presentation, investigations performed, management, and survival outcome.

In all patients with dermatomyositis, the diagnosis was made either before or concurrently with the diagnosis of GBC, likely due to the characteristic features of dermatomyositis being the presenting symptoms. The majority of patients (88.9%) presented with a facial and truncal rash, often accompanied by proximal muscle weakness. Late-stage symptoms such as dysphagia were also observed in over half of the patients (55.6%). All cases of dermatomyositis as a PNS arose in the setting of locally advanced or metastatic GBC. Extensive investigations were conducted, revealing elevated creatinine kinase levels in most patients. Serum autoantibody testing showed that 75% of patients were positive for ANA. Tumour markers were less reliable, with some patients exhibiting elevated CA-125 and carcinoembryonic antigen levels, while others had normal values. To confirm the diagnosis of dermatomyositis, electromyography, muscle biopsy, and skin biopsy were performed in some cases, with findings consistent with the diagnosis. However, in most cases, the characteristic clinical features, including dermatological manifestations and proximal muscle weakness, were sufficient for a clinical diagnosis of dermatomyositis.

Management of dermatomyositis in the context of GBC generally involves three components: immunosuppression, anticancer therapy, and surgery. Corticosteroids are the mainstay of dermatomyositis treatment and are typically administered until clinical improvement in both dermatological manifestations and muscle weakness is observed. The dosage is then tapered gradually. Other immunosuppressive agents, such as methotrexate and hydroxychloroquine, remain adjuncts. In this cohort, 77.8% of patients received immunosuppression, with methylprednisolone as the most common agent. Outcomes were positive, with 85.7% of patients showing improvement in muscle strength and/or regression of dermatological manifestations. Only one patient experienced regression of skin lesions but with concurrent progression of muscle weakness. Alternative approaches to managing dermatomyositis beyond corticosteroids have also been explored. Ni Q. F. et al. [] reported promising results using a combination therapy consisting of loratadine, cetirizine, hydroxychloroquine, magnesium isoglycyrrhizinate, vitamin C, calcium gluconate, and a coenzyme complex, resulting in gradual abatement of skin lesions []. Of note, there is some evidence [,] describing an improvement in dermatomyositis after chemotherapy, which suggests that the immunosuppressive effect of systemic chemotherapy contributes to the improvement of dermatomyositis. Anticancer treatment, in the form of chemotherapy or chemoradiotherapy, was administered to 33.3% of patients. However, many patients were ineligible for such treatments due to advanced GBC stage or advanced age. Gemcitabine and cisplatin were the most common chemotherapeutic agents used. While the specific impact of anticancer treatment could not be definitively determined, all three patients who received it ultimately passed away. Surgical intervention was performed in 44.4% of patients. Patients who underwent radical cholecystectomy exhibited more favourable outcomes compared to those who underwent exploratory laparotomy. This is aligned with the current literature indicating that exploratory laparotomy often reveals previously undetected peritoneal and liver metastases, leading to a poorer prognosis.

A case report described a 68-year-old woman with pain and muscle weakness who, despite normal immune markers like ANA, was diagnosed with polymyositis and concurrent GBC [].