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Pancreatic adenocarcinoma is a malignant neoplasm arising from the glandular epithelium of the exocrine pancreatic ducts and is by far the most common histological type of pancreatic tumour. It is characterised by highly aggressive biological behaviour, a marked tendency to invade peripancreatic structures early and a propensity for metastatic dissemination from the initial stages of the disease’s natural history. Anatomically, adenocarcinoma may develop in any segment of the gland, but it has a clear predilection for the head of the pancreas, where it tends to present with signs of biliary obstruction, whereas neoplasms of the body and tail often remain clinically silent for longer. This anatomical feature contributes substantially to the diagnostic delay observed in a significant proportion of patients.

The progression of pancreatic adenocarcinoma follows a multistep model that develops on a background of intraepithelial or cystic precursor lesions, with the progressive accumulation of genetic and epigenetic alterations that confer invasive capacity, resistance to apoptosis and adaptation to a particularly desmoplastic stromal microenvironment. In its early stages, the disease is often paucisymptomatic or asymptomatic, whereas the appearance of overt clinical signs frequently coincides with already locally advanced or metastatic disease. Consequently, only a minority of patients have potentially resectable disease at diagnosis, which has a decisive impact on overall prognosis.

Management of pancreatic adenocarcinoma requires a highly specialised multidisciplinary approach integrating expertise in medical oncology, pancreatic surgery, radiology, endoscopy, pathology and clinical nutrition. Diagnosis and staging follow a structured pathway combining high-resolution cross-sectional imaging, endoscopic procedures with cytological or histological sampling, and functional assessment of the patient. Despite advances in therapeutic strategies and systemic treatments, pancreatic adenocarcinoma remains associated with an overall poor prognosis, making attention to risk factors, early diagnosis in selected individuals and optimisation of care pathways essential.

The epidemiology of pancreatic adenocarcinoma is characterised by a relatively lower incidence than other malignancies of the digestive system, but by extremely high mortality, which consistently places it among the leading causes of cancer death in industrialised countries. Globally, incidence shows a heterogeneous geographical distribution, with higher rates in North America, Western Europe and Australia and lower rates in many regions of Africa and Asia, although these differences are also influenced by the quality of cancer registration systems and access to care. In high-income countries, pancreatic adenocarcinoma is one of the malignancies with the most unfavourable incidence-to-survival ratio, reflecting late diagnosis and the limited efficacy of treatments in advanced stages.

From a temporal perspective, a progressive increase in incidence and mortality has been observed over recent decades, partly attributable to population ageing but also to the growing prevalence of metabolic and behavioural risk factors. Age is one of the most important determinants, with peak incidence generally occurring between the sixth and eighth decades of life. The disease is rare before the age of 40, whereas the likelihood of diagnosis rises significantly with advancing age. A slight male predominance has been documented, although the sex difference is less pronounced than in other malignancies related to behavioural exposures.

Cigarette smoking is the principal modifiable risk factor for pancreatic adenocarcinoma. Numerous epidemiological studies have demonstrated a dose-dependent association between tobacco exposure and increased risk, with an effect that persists for years after cessation, although it gradually declines over time. Pathogenic mechanisms include direct exposure of pancreatic tissue to systemic carcinogens, induction of oxidative stress and activation of chronic inflammatory pathways that promote neoplastic transformation of ductal cells. Smoking cessation is therefore a central component of the primary prevention of this malignancy.

An increasingly important role is attributed to metabolic factors. Diabetes mellitus, particularly when of recent onset, is associated with an increased risk of pancreatic adenocarcinoma and may represent both a predisposing factor and an early paraneoplastic manifestation. Obesity and metabolic syndrome are also associated with increased risk, probably through mechanisms involving insulin resistance, hyperinsulinaemia, altered growth-factor signalling and a chronic low-grade inflammatory state. In this setting, body-weight control and management of metabolic disorders are relevant to risk reduction at the population level.

Chronic pancreatitis, irrespective of aetiology, is a recognised predisposing factor, with risk increasing in relation to disease duration and persistence of chronic inflammation. Hereditary forms of pancreatitis, characterised by early onset and a prolonged course, are associated with a particularly high lifetime risk. Chronic alcohol consumption, although not a direct causal factor comparable to smoking, contributes indirectly to risk through the induction of chronic pancreatitis and persistent pancreatic injury.

Alongside acquired factors, several inherited genetic conditions confer a significant predisposition to pancreatic adenocarcinoma. These include syndromes associated with BRCA1 and BRCA2 mutations, Lynch syndrome, Peutz–Jeghers syndrome and other conditions characterised by defects in DNA-repair mechanisms. In these settings, lifetime cumulative risk is substantially higher than in the general population. Familial clustering of pancreatic cancer has also been described in the absence of a defined genetic syndrome, suggesting the existence of susceptibility factors that are not yet fully understood.

Taken together, these elements delineate an epidemiological framework in which pancreatic adenocarcinoma emerges as a malignancy strongly influenced by the interaction between age, behavioural factors, metabolic disorders, chronic inflammation and genetic predisposition. Understanding these determinants is the essential basis for effective primary-prevention strategies and for identifying population subgroups at increased risk.

There are no recommended population screening programmes for pancreatic adenocarcinoma because of its relatively low incidence in the general population, the lack of sufficiently sensitive and specific non-invasive tests, and the high risk of false-positive findings that would lead to unjustified invasive diagnostic procedures. Broad screening would not be cost-effective and could expose individuals to potential harms exceeding the expected benefits. Attention therefore focuses on surveillance strategies targeted at selected groups whose risk is substantially above average.

Surveillance of high-risk individuals is the setting in which early detection of pancreatic adenocarcinoma has a rational clinical role. This category includes carriers of inherited genetic syndromes associated with high risk, such as BRCA mutations, Peutz–Jeghers syndrome and Lynch syndrome, as well as individuals with a strong family history of pancreatic cancer, particularly when several first-degree relatives are affected. In these individuals, surveillance is generally initiated at a relatively young age and tailored to the individual risk profile.

The methods most commonly used in surveillance programmes include endoscopic ultrasonography and magnetic resonance imaging with cholangiopancreatography. Endoscopic ultrasonography provides detailed assessment of the pancreatic parenchyma and ducts, with high sensitivity for small lesions, whereas magnetic resonance imaging enables non-invasive characterisation of cystic lesions and ductal abnormalities. Combined use of these techniques increases the likelihood of detecting precursor lesions or early-stage tumours while limiting exposure to ionising radiation.

Particular attention is given to patients with long-standing chronic pancreatitis, especially hereditary or early-onset forms, in whom the cumulative risk of adenocarcinoma is significantly increased. In these cases, surveillance does not follow universally standardised protocols but is tailored according to clinical history, disease duration and the presence of additional risk factors. The objective is to detect neoplastic transformation at a stage still amenable to curative treatment.

In recent years, innovative strategies for early detection have been investigated, including serum biomarkers, circulating tumour DNA analysis and artificial-intelligence approaches applied to imaging. Although these tools show promising potential, they have not yet achieved a sufficient level of evidence for routine clinical use and remain largely confined to research settings or experimental protocols.

Overall, screening for pancreatic adenocarcinoma is not indicated in the general population, whereas selective surveillance of high-risk individuals represents a targeted and rational strategy. Its effectiveness depends on accurate candidate selection, appropriate use of diagnostic techniques and integration of surveillance into structured care pathways, with the aim of advancing diagnosis without generating diagnostic or therapeutic overuse.

The biology of pancreatic adenocarcinoma, in its most common form represented by pancreatic ductal adenocarcinoma, develops from the epithelium of the pancreatic ducts in the setting of progressively disrupted tissue homeostasis. The normal exocrine pancreas is characterised by a dynamic balance among acinar, ductal and stromal cells within a finely regulated microenvironment. Prolonged exposure to injurious factors, including chronic inflammation, oxidative stress, environmental toxicants and metabolic insults, causes profound reorganisation of the epithelial and stromal compartments, predisposing to neoplastic transformation.

A central pathogenic role is played by chronic pancreatitis, which induces a continuous cycle of injury and repair with activation of pancreatic stellate cells, extracellular-matrix deposition and progressive fibrosis. In this context, precursor lesions appear, particularly pancreatic intraepithelial neoplasia (PanIN), which forms a morphological and biological continuum from low-grade PanIN to high-grade lesions preceding stromal invasion. Other recognised precursor lesions include mucinous cystic neoplasms and IPMNs, which share some molecular mechanisms with invasive adenocarcinoma.

From a genetic perspective, pancreatic adenocarcinoma is characterised by a highly defined yet complex molecular profile. Activating mutation of KRAS is the earliest and most frequent event, present in the great majority of cases, with persistent activation of the MAPK and PI3K/AKT pathways and consequent proliferative signalling independent of physiological stimuli. KRAS mutation is followed by inactivating alterations in key tumour-suppressor genes such as CDKN2A, involved in cell-cycle control, TP53, responsible for genomic surveillance, and SMAD4, a central node of the TGFβ pathway whose loss promotes invasiveness and metastatic progression. Sequential accumulation of these alterations defines the transition from precursor lesions to invasive carcinoma.

In addition to point mutations, genomic instability is common, with deletions, amplifications and complex chromosomal rearrangements. In a minority of cases, especially in hereditary-predisposition settings, alterations affect genes involved in DNA repair, such as BRCA1, BRCA2, PALB2 and ATM, creating specific biological and therapeutic vulnerabilities. These subgroups often show a distinct genomic phenotype characterised by homologous-recombination deficiency and greater sensitivity to DNA damage.

Epigenetic alterations have a complementary and crucial role in pathogenesis. Changes in DNA methylation, histone remodelling and microRNA dysregulation contribute to the silencing of tumour-suppressor genes and promotion of protumoural transcriptional programmes. MicroRNAs such as miR-21 are frequently overexpressed and associated with invasiveness and therapeutic resistance, whereas other microRNAs involved in pancreatic differentiation are reduced, favouring a less differentiated and more aggressive cellular phenotype.

The tumour microenvironment of pancreatic adenocarcinoma is one of the disease’s distinctive biological features. The neoplasm is embedded in an exceptionally abundant desmoplastic stroma rich in activated fibroblasts, stellate cells, extracellular-matrix components and immune cells. This dense stroma compresses blood vessels, generates chronic hypoxia and limits drug penetration, making a major contribution to chemoresistance. Fibroblasts and immune cells produce cytokines and growth factors, including IL-6, CXCL12, TGFβ and VEGF, which support proliferation, invasiveness and cell survival.

From an immunological perspective, pancreatic adenocarcinoma is characterised by a strongly immunosuppressive microenvironment. Cytotoxic lymphocytic infiltration is generally sparse, whereas myeloid-derived suppressor cells, tumour-associated macrophages with a protumoural phenotype and regulatory T lymphocytes are abundant. PD-L1 expression is variable but often insufficient on its own to explain the marked resistance to immunotherapy, which appears to result from a complex network of immune-exclusion mechanisms and functional T-cell inactivation.

Transcriptomic analyses have identified the principal molecular subtypes:

• classical subtype: characterised by expression of ductal-differentiation genes and better epithelial organisation;
• basal-like subtype: associated with loss of differentiation, greater aggressiveness and an unfavourable prognosis;
• immunogenic subtype, described in some cohorts, with increased expression of immune and inflammatory genes.

These profiles reflect genuine biological heterogeneity, with prognostic and potentially therapeutic implications.

From a metabolic perspective, pancreatic cancer cells display profound adaptations to hypoxia and nutrient deprivation. Aerobic glycolysis is strongly activated, but alternative strategies coexist, such as the use of glutamine through non-canonical pathways and nutrient recycling through autophagy and macropinocytosis. These mechanisms permit survival in a hostile microenvironment and contribute to resistance to oxidative stress and cytotoxic treatments.

Histologically, pancreatic ductal adenocarcinoma is characterised by irregular glands embedded in abundant fibrous stroma. Well-differentiated forms show recognisable glandular structures with mucin production, whereas moderately and poorly differentiated variants have disorganised architecture, marked nuclear pleomorphism and a high mitotic index. Histological variants, such as adenosquamous or mucinous forms, are less common but are associated with aggressive biological behaviour.

Immunohistochemistry supports diagnosis and characterisation: CK7, CK19 and MUC1 are commonly expressed, whereas Ki-67 provides an estimate of proliferation. Assessment of perineural invasion, which is particularly frequent, and lymphovascular invasion provides distinctive morphological evidence of the tumour’s infiltrative capacity.

Overall, pancreatic adenocarcinoma emerges as a malignancy of high biological complexity, determined by the interaction of early genetic mutations, epigenetic remodelling, a desmoplastic stromal microenvironment, extreme metabolic adaptations and profound immunosuppression. These elements explain its marked aggressiveness, early tendency to spread and resistance to conventional treatments.

The clinical manifestations of pancreatic adenocarcinoma are often late and non-specific, reflecting the initially silent growth of the tumour and the retroperitoneal location of the organ. In the early stages, the neoplasm may produce no overt symptoms or may present with vague complaints that rarely suggest pancreatic disease, thereby contributing to the diagnostic delay characteristic of this malignancy.

One of the most frequent symptoms is abdominal pain, typically located in the epigastric or mid-abdominal region and often radiating posteriorly to the back. Pain may initially be intermittent and mild but tends to become progressively continuous and severe as the lesion enlarges and infiltrates peripancreatic neural structures. Invasion of the coeliac nerve plexus is one of the principal causes of severe, refractory pain in advanced disease.

Weight loss is very common and often occurs early, resulting from the combination of reduced food intake, maldigestion and tumour-induced metabolic alterations. It is frequently accompanied by anorexia, early satiety and marked fatigue. Exocrine pancreatic insufficiency secondary to ductal obstruction or destruction of the parenchyma may cause steatorrhoea, bulky foul-smelling stools and further weight loss.

In tumours located in the pancreatic head, compression or infiltration of the common bile duct causes obstructive jaundice, often accompanied by dark urine, pale stools and intense pruritus. Jaundice may be the most evident presenting symptom and frequently prompts diagnostic investigation. In tumours of the body and tail, jaundice is generally absent and the disease tends to present later with pain and weight loss.

Clinical presentation varies according to tumour location:

• tumours of the pancreatic head: obstructive jaundice, pruritus, cholangitis and epigastric pain;
• tumours of the body: back pain, weight loss and non-specific symptoms;
• tumours of the tail: late presentation, often with locally advanced or metastatic disease.

Metabolic changes such as new-onset diabetes mellitus or sudden deterioration of pre-existing diabetes may precede the diagnosis of pancreatic adenocarcinoma and represent an important clinical warning sign, particularly in adults without evident metabolic risk factors. This phenomenon is attributed to tumour interference with pancreatic endocrine function and insulin sensitivity.

Local progression may lead to invasion of adjacent structures, including the duodenum, stomach, transverse colon and mesenteric vessels, with the development of nausea, vomiting, intestinal obstruction and signs of segmental portal hypertension. Vascular infiltration also contributes to surgical unresectability in a substantial proportion of patients at diagnosis.

Metastatic dissemination occurs early and most commonly involves the liver, peritoneum and lungs. Liver metastases may cause hepatomegaly, right-upper-quadrant pain and progressive liver failure, whereas peritoneal carcinomatosis is associated with ascites, abdominal distension and deterioration of nutritional status. Cancer cachexia, with marked loss of muscle mass and functional decline, is common in advanced disease.

A minority of patients may develop paraneoplastic syndromes, including migratory thrombophlebitis, hypercoagulability and thromboembolic events, reflecting tumour-induced systemic activation of coagulation. When associated with abdominal symptoms and weight loss, these manifestations should raise diagnostic suspicion.

On physical examination, in addition to jaundice and evidence of nutritional impairment, abdominal tenderness, hepatomegaly and, in advanced cases, ascites may be present. The typical clinical picture is that of an adult or older patient with epigastric pain radiating to the back, significant weight loss, fatigue and, in tumours of the pancreatic head, progressively worsening jaundice.

The diagnostic assessment of pancreatic adenocarcinoma begins with a well-founded clinical suspicion and proceeds through a sequence of investigations aimed first at morphological confirmation of the neoplasm, then at excluding alternative diagnoses and finally at defining disease extent, without yet introducing formal staging. Clinical suspicion typically arises in the presence of progressive obstructive jaundice, epigastric pain radiating posteriorly, unintentional weight loss, anorexia, steatorrhoea, new-onset or rapidly worsening diabetes, marked fatigue and pruritus. In some cases, onset is insidious, with non-specific symptoms that delay diagnosis. Risk is increased in individuals with cigarette smoking, chronic pancreatitis, long-standing diabetes mellitus, obesity, a family history of pancreatic neoplasms or predisposing genetic syndromes. In this context, the aim of initial clinical assessment is to recognise a suggestive presentation promptly and refer the patient for high-yield diagnostic investigations.

Laboratory tests provide initial support but cannot establish a definitive diagnosis. The biochemical profile may show cholestasis with elevated bilirubin, alkaline phosphatase and gamma-glutamyl transferase in tumours of the pancreatic head, altered nutritional markers and occasionally anaemia. CA 19-9 may be elevated and support clinical suspicion, but it has no independent diagnostic value and is not specific, as it may be normal in early disease or elevated in benign conditions. Blood tests must therefore be interpreted as contextual evidence rather than diagnostic criteria.

The cornerstone of initial assessment is contrast-enhanced computed tomography performed using a triphasic pancreatic protocol. This examination identifies the primary lesion, assesses its size and relationship to vascular structures, and detects possible signs of advanced disease. Adenocarcinoma typically appears as a hypoattenuating mass with irregular margins, associated with dilatation of the main pancreatic duct and sometimes the common bile duct, producing the so-called double-duct sign. CT is the first-line tool for directing diagnostic suspicion and selecting subsequent investigations.

Magnetic resonance imaging with magnetic resonance cholangiopancreatography (MRCP) is a complementary examination that is particularly useful in equivocal cases or when CT is inconclusive. MRI provides better characterisation of parenchymal and ductal lesions, accurate assessment of the biliary and pancreatic ducts, and more precise distinction between a solid neoplasm, focal pancreatitis and other inflammatory conditions. MRCP also defines the level and degree of ductal obstruction without invasive procedures.

Endoscopic ultrasonography (EUS) is the most sensitive investigation for diagnosing small pancreatic lesions and for detailed assessment of the tumour and peripancreatic tissues. During EUS, endoscopic ultrasound-guided fine-needle aspiration (FNA) or core-needle biopsy (FNB) can be performed to obtain cytological or histological material for diagnostic confirmation. EUS is particularly indicated when CT or MRI does not provide a definitive diagnosis or when morphological confirmation is required before systemic or neoadjuvant treatment.

Pathological analysis of samples obtained by FNA or FNB enables definitive diagnosis of pancreatic ductal adenocarcinoma. Haematoxylin-and-eosin examination shows infiltrating atypical glands embedded in marked desmoplastic stroma, with nuclear pleomorphism, cytological atypia and variable mitotic activity. The pathologist assesses the degree of differentiation and the presence of necrosis. In cases with non-specific morphology, immunohistochemistry may support the diagnosis and distinguish adenocarcinoma from neuroendocrine neoplasms, acinar tumours or metastases from other sites, integrating the findings with the clinical and radiological context.

According to the principal international guidelines, a minimum set of clinical, radiological and pathological information must be available before pancreatic adenocarcinoma can be considered diagnosed and treatment decisions made; these elements are not formal “diagnostic criteria” but represent the essential requirements for a reliable diagnosis:

Elements required to establish a diagnosis of pancreatic adenocarcinoma

• Radiological identification of a suspicious solid pancreatic lesion by CT or MRI.
• Consistency between the clinical presentation and imaging findings.
• Cytological or histological confirmation by EUS-guided FNA or FNB, when indicated.
• Exclusion of alternative diagnoses such as focal pancreatitis, neuroendocrine neoplasms or metastases.
• Multidisciplinary integration of clinical, radiological and pathological data.

The differential diagnosis must be approached systematically. The principal conditions to distinguish include focal chronic pancreatitis and autoimmune pancreatitis, both of which may mimic a neoplastic mass; in these cases, combined assessment of imaging, response to corticosteroid therapy and histology permits discrimination. Pancreatic neuroendocrine neoplasms, acinar-cell tumours, cystic neoplasms with a solid component and pancreatic metastases must also be considered, as these entities have different biological and prognostic characteristics and require specific therapeutic approaches.

Once the diagnosis has been confirmed, investigations focus on assessment of disease extent. Contrast-enhanced CT remains central for evaluating vascular relationships and identifying liver or peritoneal metastases. 18F-FDG PET is not routinely indicated but may be useful in selected cases to identify metastatic sites not apparent on CT or to clarify equivocal findings. In the presence of significant obstructive jaundice, endoscopic procedures such as ERCP may be required therapeutically for biliary drainage, but not as the primary diagnostic procedure.

In summary, diagnostic assessment of pancreatic adenocarcinoma follows a practical sequence: clinical suspicion; pancreatic-protocol CT; complementary MRI when required; endoscopic ultrasonography with sampling when indicated; morphological confirmation; definition of the differential diagnosis; and then assessment of disease extent by cross-sectional imaging.

Staging of pancreatic adenocarcinoma synthesises the information obtained during diagnostic assessment and provides a standardised description of the anatomical extent of disease, distinguishes potentially resectable forms from locally advanced or metastatic disease, and offers prognostic guidance. The international reference system is the AJCC/UICC TNM, currently in its eighth edition, which classifies disease according to the characteristics of the primary tumour, lymph-node involvement and the presence of distant metastases.

Clinical cTNM staging is based primarily on imaging. Contrast-enhanced computed tomography is essential for assessing tumour size, involvement of the major vascular axes and the presence of metastases. The relationship of the tumour to the superior mesenteric artery, common hepatic artery, coeliac trunk and portal vein is a key element in defining resectability. MRI and, in selected cases, PET help complete the assessment when uncertainty remains regarding disease extent.

In pancreatic carcinoma, the principal determinants of prognosis are surgical resectability, nodal status and the presence of metastases. The TNM system organises anatomical progression along a spectrum ranging from localised, potentially resectable disease to systemic dissemination. In clinical practice, however, classification as resectable, borderline resectable, locally advanced unresectable or metastatic disease has immediate decision-making relevance.

Conceptually, the principal stage groups may be summarised as follows:

Principal stage groups in pancreatic adenocarcinoma (AJCC/UICC)

• Stage I: tumour confined to the pancreas, limited in size, with no lymph-node or distant metastases.
• Stage II: more locally extensive tumour and/or regional lymph-node involvement, without distant metastases.
• Stage III: locally advanced disease with extensive vascular or nodal involvement, unresectable, without distant metastases.
• Stage IV: distant metastases, most commonly involving the liver and peritoneum.

When a surgical specimen is available, pathological pTNM staging permits more accurate prognostic assessment through direct measurement of tumour size, the number of lymph nodes examined and involved, resection-margin status, and the presence of vascular or perineural invasion. A clear resection margin is one of the principal determinants of a favourable outcome, whereas microscopic residual disease is associated with a poor prognosis.

Survival curves show a close relationship between stage and outcome. In resectable disease treated with surgery and adjuvant therapy, 5-year survival remains limited but is significantly higher than in advanced disease. In locally advanced and metastatic disease, prognosis is markedly poor, with median survival measured in months despite advances in systemic therapies.

In addition to TNM, several additional prognostic factors modulate individual risk. Important tumour-related factors include histological grade, perineural and vascular invasion, and the number of metastatic lymph nodes. Patient-related factors such as performance status, nutritional status, weight loss and imaging-documented sarcopenia significantly influence treatment tolerance and overall outcome. Systemic inflammatory markers and nutritional indices have been associated with prognostic differences in numerous cohorts.

Overall, staging of pancreatic adenocarcinoma is an integrated process combining anatomical extent, the feasibility of resection and the patient’s general condition. Prognosis remains guarded in early disease but is significantly better than in advanced stages, whereas in metastatic disease the clinical objective focuses primarily on symptom control and preservation of quality of life.

Treatment of pancreatic adenocarcinoma is based on a complex multimodal strategy that depends heavily on disease stage, anatomical resectability, the tumour’s biological characteristics and the patient’s general condition. Management should be centralised in high-volume centres and must be agreed within a multidisciplinary team integrating medical oncology, pancreatic surgery, radiotherapy, interventional radiology, gastroenterology, clinical nutrition and supportive care.

Operationally, patients are divided into four broad categories: resectable disease, borderline resectable disease, locally advanced unresectable disease and metastatic disease. This classification guides the entire therapeutic pathway and reflects the tumour’s relationship with the major vascular axes, particularly the superior mesenteric artery, coeliac trunk, portal vein and superior mesenteric vein.

In patients with resectable disease, surgery is the only potentially curative option, but it is now clear that surgery alone is insufficient. The standard approach consists of radical surgical resection followed by adjuvant chemotherapy. The surgical procedure depends on tumour location: pancreaticoduodenectomy is indicated for neoplasms of the pancreatic head, whereas distal pancreatectomy, with or without splenectomy, is reserved for tumours of the body and tail. The objective is an R0 resection combined with adequate lymphadenectomy, both of which are major determinants of prognosis.

Adjuvant chemotherapy is recommended for all patients who recover adequately from surgery. Regimens based on modified FOLFIRINOX have demonstrated a significant improvement in overall survival compared with gemcitabine in patients with good performance status, whereas gemcitabine alone or combined with capecitabine is an alternative for frailer individuals. Initiation of adjuvant treatment requires careful assessment of nutritional and functional recovery, which is often impaired after major pancreatic surgery.

For borderline resectable tumours, the preferred approach is neoadjuvant chemotherapy, with or without radiotherapy. The goals are to reduce tumour volume, treat occult micrometastases early and increase the likelihood of complete resection. Intensive regimens such as FOLFIRINOX are frequently used in patients with adequate functional reserve, followed by radiological reassessment to confirm surgical feasibility. Careful patient selection is crucial in this setting to avoid futile surgery in biologically aggressive disease.

Radiotherapy in the neoadjuvant or adjuvant setting remains subject to case-by-case selection. Modern techniques permit targeted conformal or stereotactic treatment aimed at improving local control in selected patients, particularly when high-risk margins or borderline vascular involvement persist. Its use must be balanced against the risk of toxicity to adjacent radiosensitive structures.

In patients with locally advanced unresectable disease, treatment is predominantly systemic. First-line chemotherapy aims to control disease, relieve symptoms and, in a minority of cases, achieve sufficient tumour regression to permit secondary resection. FOLFIRINOX or gemcitabine plus nab-paclitaxel are the most commonly used options. In patients who achieve prolonged disease stability, consolidative radiotherapy may be considered for local control.

In metastatic disease, the aim of treatment is palliative. Therapeutic choices depend on performance status and disease burden. FOLFIRINOX and gemcitabine plus nab-paclitaxel are standard first-line regimens for eligible patients, whereas gemcitabine monotherapy may be used in frailer individuals. Subsequent lines include fluoropyrimidines, liposomal irinotecan and other cytotoxic regimens selected according to tolerance and previous response.

A subgroup of patients may benefit from targeted therapies. Germline or somatic BRCA mutations or homologous-recombination defects may make PARP inhibitors appropriate as maintenance therapy after response to platinum-based chemotherapy. Other molecular alterations are rare, but genomic profiling may be considered in advanced disease.

Nutritional and symptomatic support is an indispensable component of treatment. Pancreatic adenocarcinoma is frequently associated with malnutrition, cachexia and exocrine pancreatic insufficiency. Enzyme replacement, individualised dietary support and pain control, which is often complex, are essential to treatment tolerance and quality of life. Early involvement of palliative care is recommended and should not be limited to the terminal stages of disease.

Follow-up and post-treatment surveillance in pancreatic adenocarcinoma have different objectives from those in many other solid tumours, reflecting the high risk of recurrence and the frequent presence of functional sequelae. Follow-up is directed toward early detection of recurrent disease, monitoring of late treatment complications and preservation of the patient’s nutritional and functional status.

In patients who have undergone curative-intent surgical resection, the risk of recurrence is highest during the first two years. Clinical reviews are generally scheduled every 3–6 months and include symptom assessment, physical examination and monitoring of nutritional status. Contrast-enhanced computed tomography of the chest and abdomen is the reference examination for radiological surveillance, whereas serum markers, particularly CA 19-9, may provide complementary information despite limitations in sensitivity and specificity.

During adjuvant and post-adjuvant follow-up, it is essential to distinguish late treatment toxicity from signs of recurrence. Liver-test abnormalities, persistent gastrointestinal symptoms and abdominal pain require careful assessment to avoid diagnostic delay. Imaging is repeated at regular intervals or brought forward when clinical suspicion arises.

In patients treated with neoadjuvant chemotherapy followed by surgery, follow-up incorporates assessment of the pathological response and resection-margin status, both of which are relevant prognostic factors. In this setting too, surveillance is more intensive during the first years and is gradually spaced out in patients who remain disease-free.

For patients with locally advanced or metastatic disease, follow-up largely overlaps with monitoring of treatment response. Clinical and radiological assessments are performed at regular intervals to document stability, response or progression and to guide decisions regarding subsequent lines of therapy or intensification of palliative support.

Management of functional sequelae is a central aspect of follow-up. Secondary diabetes, exocrine pancreatic insufficiency and chronic digestive disorders may develop after pancreatic surgery. Metabolic monitoring, adjustment of enzyme-replacement therapy and ongoing nutritional support are essential to prevent weight loss and sarcopenia.

The overall duration of follow-up in resected patients is generally at least five years, with greater intensity during the first two years. In patients with advanced disease, follow-up is more flexible and centred on symptom control, treatment adjustment and preservation of quality of life.

In summary, follow-up of pancreatic adenocarcinoma is not limited to oncological surveillance but represents a continuous process of comprehensive care integrating disease monitoring, complication management, and nutritional and palliative support throughout the entire clinical course.

Long-term quality-of-life considerations are a crucial component of comprehensive care for patients with pancreatic adenocarcinoma, given the intensity of treatment and the frequent persistence of functional and systemic consequences. In patients undergoing curative-intent surgical resection, as well as in those receiving prolonged systemic therapy, quality of life is often affected by digestive, metabolic and psychological sequelae that require structured, continuous assessment.

A central domain is digestive and exocrine pancreatic function. After pancreatectomy, particularly pancreaticoduodenectomy, exocrine pancreatic insufficiency is extremely common and manifests with steatorrhoea, bloating, chronic diarrhoea and malabsorption. These disorders affect daily independence and social life and require adequate, individualised enzyme replacement in addition to regular clinical monitoring.

Metabolic alterations, particularly pancreatogenic diabetes, represent a significant sequela. Loss of pancreatic endocrine tissue and hormonal changes induced by surgery or disease progression may cause glycaemic instability, affecting daily management and general well-being. Metabolic control often requires a multidisciplinary approach and long-term follow-up.

Nutrition and body composition directly influence quality of life. Unintentional weight loss, reduced muscle mass and malnutrition are common even after curative treatment and are associated with impaired functional capacity, fatigue and greater vulnerability to infection. Ongoing nutritional support, with monitoring of body composition and calorie-protein intake, is essential to preserve independence and quality of life.

Chronic pain, of neuropathic or visceral origin, may persist even in the absence of active disease as a consequence of surgery or post-treatment fibrosis. This symptom affects sleep, physical activity and mood and requires integrated, individualised pain-control strategies.

The psychological and psychosocial domain is also highly relevant. Pancreatic adenocarcinoma has a major emotional impact related to the perceived prognosis, fear of recurrence and the burden of chronic functional sequelae. Anxiety, depression and psychological distress may persist over the long term, affecting family and social relationships and making structured psychological support necessary.

Overall, long-term quality of life in pancreatic adenocarcinoma depends on the healthcare system’s ability to provide integrated care that combines oncological surveillance with management of digestive, metabolic, nutritional and psychological sequelae. In this context, quality of life is a fundamental clinical outcome and should be considered alongside survival indicators when assessing the overall effectiveness of treatment.

Complications of pancreatic adenocarcinoma arise from the interaction between disease progression, surgical treatments and systemic therapies, creating a complex clinical picture that requires continuous multidisciplinary management. Even in early stages, biliary obstruction and impaired pancreatic function may cause jaundice, pruritus, malnutrition and deterioration of general condition.

Local progression of the tumour may cause persistent abdominal pain, compression of vascular and biliary structures, and duodenal obstruction with nausea, vomiting and inability to tolerate oral intake. Invasion of the retroperitoneal nerve plexuses is a major cause of severe, refractory pain. In advanced disease, cachexia, venous thromboembolism and organ failure contribute to overall clinical deterioration.

Pancreatic surgery carries a significant risk of complications. Postoperative pancreatic fistula is one of the most frequent and feared events and may progress to abscesses, sepsis and haemorrhage. Intra-abdominal infectious complications, delayed gastric emptying and postoperative bleeding affect morbidity and length of hospital stay. Persistent exocrine and endocrine pancreatic insufficiency may develop in the longer term.

Systemic therapies are associated with acute and cumulative toxicity. Cytopenias increase the risk of infection and bleeding, whereas peripheral neuropathy, diarrhoea, nausea and fatigue impair quality of life and treatment tolerability. In frail patients, these toxicities may necessitate dose reductions or premature discontinuation.

Endoscopic and interventional procedures, frequently used to treat obstructive jaundice or pain, carry specific risks. Biliary stent placement may be complicated by cholangitis, pancreatitis, stent occlusion or migration. Ablative or neurolytic procedures may be associated with transient pain, bleeding or infection.

At the systemic level, cancer cachexia, opportunistic infections and thromboembolic events are frequent and prognostically relevant complications. Progressive functional decline requires a comprehensive approach integrating early symptom control, nutritional support and, when indicated, palliative care.

Effective management of complications is based on structured prevention, including early nutritional assessment, metabolic monitoring, pain control, surveillance of treatment toxicity and prompt recognition of infection. Integration of multidisciplinary expertise reduces the severity of adverse events, improves quality of life and optimises continuity of treatment pathways.