Prognostic outcomes are inferior. Five year survival rate appears at 6% and varies from 2% to 9%. Ductal adenocarcinoma pancreas (NOS) exemplifies categorical driver genetic mutations. KRAS (> 95%) genomic mutation is a predominant, preliminary event occurring during carcinogenesis. Besides, genetic mutations within CDKN2A (p16) (95%), TP53 (50% to 80%) or SMAD4 (55%) may be discerned.  Overexpression of HER2 (>50%) may occur. Several core signalling pathways appear incriminated in carcinogenesis. Around ~10% pancreatic carcinomas demonstrate a familial mode of disease inheritance [1,2]. A male predominance is observed with male to female proportion of 1.13:1.  Ductal adenocarcinoma pancreas (NOS) commonly emerges with head of pancreas (60% to 70%), body of pancreas (5% to 15%) or tail of pancreas (10% to 15%) [1,2]. Neoplasms occurring within head of pancreas manifest distention of biliary tree, progressive jaundice and extension beyond pancreas upon initial tumour discernment. Neoplasms confined to body or tail of pancreas typically appear enlarged upon initial tumour detection. Cogent clinical symptoms are delayed. Distant metastasis is frequent and around 25% instances depict peripheral venous thrombi.

Exceptionally, tumefaction may emerge from heterotopic pancreatic tissue situated within the gastrointestinal tract. Invasive ductal adenocarcinoma pancreas (NOS) is preceded by definitive precursor lesions denominated as pancreatic intraepithelial neoplasia (PanIN), intra-ductal papillary mucinous neoplasms (IPMN) or mucinous cystic pancreatic neoplasms (MCN). Factors contributing to emergence of ductal adenocarcinoma pancreas (NOS) appear as consumption of tobacco, alcohol, enhanced dietary intake of saturated fat, obesity, chronic pancreatitis or diabetes mellitus. Hereditary syndromes as Peutz-Jeghers syndrome, hereditary pancreatitis, familial atypical multiple mole melanoma (FAMMM), familial pancreatic cancer, Lynch syndrome, familial breast cancer and Fanconi anaemia genes or familial adenomatous polyposis (FAP) may induce the neoplasm [1,2]. Ductal adenocarcinoma pancreas (NOS) is associated with cogent clinical symptoms as pain with dorsal or lumbar region, loss of weight, malaise, hyperbilirubinemia or diabetes mellitus [1,2].  

‘Trousseau sign’ is denominated by migratory thrombophlebitis, is encountered within 10% instances and arises due to tumefaction or platelet aggregating factors and procoagulants which induce tumour necrosis. Discernible thrombophlebitis is associated with arterial and venous thrombi. Pancreatitis may coexist in ~10% instances [1,2]. Tumour metastases is encountered within localized, regional lymph nodes wherein microscopic metastases occurs within 75% of stage T1 or stage T2 tumours.  Metastasis within supraclavicular lymph node may appear as an initial, representing symptom. Besides, metastasis within hepatic or renal parenchyma, peritoneum, adrenal glands, bone or distal lymph nodes may ensue. Metastases into ovarian stroma may simulate primary mucinous ovarian tumour.  Tumour dissemination may occur along guided fine needle aspiration or core needle biopsy track [1,2]. Upon gross examination, a white/ grey, sclerotic, inadequately defined tumefaction is observed. Majority (> 75%) of ductal adenocarcinoma pancreas (NOS) manifest as solid tumours. Around 25% neoplasms confined to head of pancreas   extend towards duodenal wall whereas ~20% incriminated subjects demonstrate multiple tumours [2,3].

Distinction between neoplasms originating from pancreas, ampulla or common bile duct may be challenging in advanced tumours. Frozen section is optimally adopted to confirm the disease, establish extent of possible vascular resection, tumour infiltration with precise surgical margins along with status of tumour metastasis within extra-regional lymph nodes and distant metastatic sites [2,3].

Upon low power, disorganized distribution of ducts with ill-defined perimeter, focal necrosis and mitotic activity is discerned. Surgical margins of pancreatic neck, distal pancreatic parenchyma, bile duct and uncinate process of pancreas necessitate evaluation. Ductal adenocarcinoma pancreas (NOS) exhibits anisonucleosis minimally within a singular gland with ~4:1 variation in nuclear magnitude, perineural invasion, occurrence of tumour gland adjacent to large vessels or singular file of infiltrating tumour cells(2,3). Cytological smears obtained with endoscopic ultrasound (EUS/FNA) appears as a sensitive (>90%) and specific (100%) technique for evaluating the neoplasm. Besides, thin prep smears or endoscopic brushings are sensitive (50%) in discerning the tumour. Evaluation of duodenal secretions is ~80% sensitive in discerning neoplasms of head of pancreas and ~33% sensitive in delineating tumours of tail of pancreas. Smears obtained from juice of endoscopic retrograde cholangiopancreatography (ERCP) is ~ 50% to 85% sensitive in diagnosing ductal adenocarcinoma pancreas (NOS). Cellular cytological aspirates appear devoid of acinar cells and demonstrate sheets of atypical ductal cells configuring a ‘drunken honeycomb’ pattern. Cellular clusters or singular neoplastic cells are comprised of cells with proportionately significant anisonucleosis (4:1). Signet ring cells are discerned. Mitotic figures may appear [2,3]. Papanicolaou Society of Cytopathology delineates a tiered classification for categorizing cytology of pancreatobiliary system denominated as~non diagnostic smears absence of malignant cells  atypical cells neoplastic cells cells suspicious for malignancy  malignant cells [2,3] Upon microscopy, ductal adenocarcinoma pancreas(NOS) exemplifies infiltrative, well formed to poorly formed glandular articulations or ductal structures encompassed within a significantly desmoplastic stroma.     

In contrast to neoplasms demonstrating acinar or neuroendocrine differentiation, ductal adenocarcinoma pancreas (NOS) is specifically associated with mucin secretion. Majority (90%) of neoplasms configured of well differentiated glandular structures depict perineural invasion. An estimated 50% ductal adenocarcinoma pancreas (NOS) demonstrate foci of angiolymphatic invasion wherein vascular invasion may simulate foci of pancreatic intraepithelial neoplasia (PanIN) [2,3]. Well differentiated ductal adenocarcinoma denominates a pink apical band comprised of mucin granules in association with irregular outline and distribution of neoplastic glands. Epithelial tumour cells layering neoplastic glands display loss of polarity, significant nuclear pleomorphism and conspicuous nucleoli. Mitotic figures are numerous. Surrounding stroma is desmoplastic. Majority of neoplasms appear moderately differentiated to poorly differentiate and are comprised of abortive tubular structures with prominent mitotic activity.  Tumour demonstrates infiltrative growth pattern with deep seated neoplastic glands exhibiting irregular or abortive secretion of mucin. Following neoadjuvant chemotherapy, neoplasm exhibits variable quantities of residual tumour embedded within a densely fibrotic tumour bed. Perineural space and duodenal wall may delineate residual neoplastic glands. Fibrotic foci appear blue/grey which are indicative of adjacent residual tumour. Neoplastic cells may appear as vacuolated or eosinophilic [2,3]. Variants of ductal adenocarcinoma pancreas (NOS) as denominated by World Health Organization (WHO) are designated as adenosquamous carcinoma and squamous cell carcinoma colloid carcinoma hepatoid carcinoma medullary carcinoma invasive micropapillary carcinoma signet ring cell or poorly cohesive cell  carcinoma undifferentiated carcinoma  as anaplastic, sarcomatoid or carcinosarcoma undifferentiated carcinoma with osteoclast-like giant cells [2,3].   

Variants of ductal adenocarcinoma pancreas (NOS) lacking categorization by World Health Organization (non-WHO) demonstrate neoplastic patterns as clear cell variant exhibits glandular, ductal or nested structures coated with singular layer of polygonal cells with distinct cellular perimeter and variable nuclear atypia. Clear cells are devoid of accumulation of glycogen or mucin. Upon immunohistochemistry, neoplastic cells overexpress hepatocyte nuclear factor1 beta (HNF1β). Foamy gland variant exemplifies neoplastic configuration akin to benign tumour and demonstrates well-formed glandular articulations coated by bland, uniform neoplastic cells. Tumour infiltration is subtle. Tumour cells depict abundant, foamy, whitish, micro-vesicular cytoplasm with a distinctive, pink, brush border-like zone confined to  apical  or luminal segment and  dense, wrinkled, ‘raisinoid’,  basal  nuclei. Intracellular foamy substance is comprised of regular mucigen granules which lack staining with mucin stains. Foamy pancreatic intraepithelial neoplasia (PanIN) is warranted to be a precursor lesion of ductal adenocarcinoma pancreas (NOS) [2,3]. Large duct variant configures < 10% of ductal adenocarcinoma pancreas (NOS) and is constituted of clustered ducts with irregular, jagged contours. Duct diameter varies from 0.5 millimetres to 1 centimetre. Circumscribing stroma is desmoplastic or myxoid and intermingled with intraluminal neutrophils and granular debris.  Focal microcystic areas ensue due to marked ectasia of infiltrating neoplastic glands wherein microcystic appearance is emphasized adjacent to duodenal muscularis propria. Also, a papillary pattern may be discerned vacuolated variant configures high grade tumours composed of clusters of neoplastic cells imbued with large vacuoles, thereby imparting a cribriform tumour architecture which may simulate mature adipocytes or signet ring cells. Neoplastic cells are permeated with atypical, enlarged, hyperchromatic nuclei.  Microcysts may be pervaded with cellular debris and mucin. Aforesaid articulations appear reminiscent of fat necrosis or lipogranuloma encountered within lymph nodes [2,3]. Upon ultrastructural examination, neoplastic cells appear imbued with mucigen granules [2,3].

Figure 1: Ductal adenocarcinoma pancreas(NOS)demonstrating well differentiated neoplastic glands comprised of multi-layered, mucin secreting, atypical columnar epithelium with loss of polarity, significant nuclear pleomorphism, conspicuous nucleoli and mitotic figures(6).

Figure 2: Ductal adenocarcinoma pancreas (NOS)delineating moderately differentiated neoplastic glands with multi-layered, mucin secreting atypical columnar epithelium with loss of polarity, nuclear pleomorphism, prominent nucleoli and mitotic figures(7).

Tumour grading is contingent to extent of glandular differentiation and is designated as

• Grade I (G1): Tumour is well differentiated and comprised of > 95% glandular articulations
• Grade 2 (G2): Tumour is moderately differentiated and constituted of 50% to 95% glandular structures
• Grade 3 (G3): Tumour is poorly differentiated and composed of < 50% glandular configurations [3, 4].

TNM staging of ductal adenocarcinoma pancreas (NOS) is denominated as

• TX: Primary tumour cannot be assessed
• T0: No evidence of primary tumour
• Tis: Carcinoma in situ
• T1: Tumour ≤2 centimetres magnitude and confined to pancreas  
• T1 a : Tumour magnitude <0.5 centimetres
• T1b: Tumour magnitude >0.5 centimetres and <1 centimetre
• T1c : Tumour  magnitude > 1 centimetre and < 2 centimetres  
• T2: Tumour magnitude > 2 centimetres and < 4 centimetres and  confined to pancreas                                                                                   
• T3: Tumour magnitude > 4 centimetres and extends beyond pancreas. Major arteries or veins abutting pancreas are spared
• T4: Tumour extends beyond pancreas into major arteries or veins adjacent to pancreas. Upon surgical resection, tumour eradication is incomplete.

Regional lympy nodes

• NX: Regional lymph nodes cannot be assessed
• N0: Regional lymph node metastasis absent
• N1: Regional lymph node metastasis into one to three lymph nodes
• N2: Regional lymph node metastasis into ≥4 lymph nodes.

Distant Metastasis

• M0: Distant metastasis absent
• M1: Distant metastasis present into distant lymph nodes, hepatic and pulmonary parenchyma or peritoneal cavity [3,4].

Staging of ductal adenocarcinoma pancreas (NOS) is denominated as

• stage 0: Carcinoma in situ (Tis, N0, M0)
• Stage IA: Tumour is ≤2 centimetres and confined to pancreas. Regional lymph node or distant metastasis absent (T1, N0, M0)
• Stage IB: Tumour is >2 centimetres and confined to pancreas. Regional lymph node and distant metastasis absent (T2, N0, M0)
• Stage IIA: Tumour is > 4 centimetres and extends beyond pancreas. Regional lymph nodes, adjacent arteries, veins or distant metastasis is absent (T3, N0, M0)
• Stage IIB: Tumour of variable magnitude with absence of metastasis into adjacent arteries or veins. One to three regional lymph nodes are incriminated with tumour dissemination. Distant metastasis is absent (T1, T2 or T3, N1, M0)
• Stage III: Tumour of variable magnitude with metastasis into ≥4 regional lymph nodes. Tumour dissemination into adjacent arteries or veins is absent. Distant metastasis is absent (T1, T2 or T3, N2, M0) OR tumour dissemination into adjacent arteries and veins with regional lymph node metastasis. Distant metastasis is absent (T4, any N, M0)                           
• Stage IV: Tumour of variable magnitude with regional lymph node and distant metastasis (any T, any N, M1) [3,4].

Recurrent Carcinoma is denominated as carcinoma which reappears following treatment and necessitates additional evaluation [3,4]. Ductal adenocarcinoma pancreas (NOS) is immune reactive to maspin, placental S100(S100P),  IMP3, p53, CK7, CK8,

CK18, CK19, MUC1, MUC3, MUC4, MUC5AC, CEA,  B72.3, CA19-9 or CA125. Ductal adenocarcinoma pancreas (NOS) is immune non-reactive to pVHL, SMAD4 / DPC4, CK20, vimentin, MUC2, synaptophysin, chromogranin, trypsin, chymotrypsin or lipase [4,5]. Ductal adenocarcinoma pancreas (NOS) requires segregation from neoplasms such as ampullary adenocarcinoma, cholangiocarcinoma, gastric carcinoma or distal bile duct adenocarcinoma. Besides, conditions such as acute pancreatitis, chronic pancreatitis, cholangitis, cholecystitis, choledochal cyst or peptic ulcer disease necessitate distinction [4,5]. Preoperative or pre-treatment assessment of the neoplasm is optimally achieved with endoscopic ultrasound guided fine needle aspiration (EUS/FNA). Alternatively, surgical resection specimen can be examined histologically for cogent disease discernment [4,5]. Ductal adenocarcinoma pancreas (NOS) can be appropriately assessed with serum levels of CA19-9 or carcinoembryonic antigen (CEA). Upon computerized tomography, majority (~92%) of neoplasms represent as a hypodense tumefaction. Tumours confined to head of Majority (85%) of ductal adenocarcinoma pancreas (NOS) appear unamenable to alleviation upon surgical resection. Neoplasms confined to head of pancreas or periampullary tumours may be subjected to Whipple’s resection, comprised of subtotal pancreaticoduodenectomy, a procedure which is associated with a perioperative mortality of ~2%. Neoplasms confined to body or tail of pancreas are treated with distal pancreatectomy. Resection of retroperitoneal nerves and lymph nodes is recommended for stage I or stage II neoplasms in order to decimate localized tumour reoccurrence [4,5]. Palliative therapeutic strategies as bypass surgical manoeuvers, chemotherapy and radiation therapy may be optimally employed. Typically, upon initial disease discernment ~52% pancreatic carcinoma demonstrate distant metastasis and~23% neoplasms display localized tumour spread [4,5]. Prognostic outcomes of ductal adenocarcinoma pancreas (NOS) are contingent to factors such as tumour magnitude and tumour stage. Neoplasms beneath <4.5 centimetre magnitude which are amenable to surgical resection are associated with favourable prognostic outcome. Neoplasms with elevated histological grade demonstrating a squamous component, perineural or vascular invasion are accompanied by unfavourable prognosis. Tumefaction with squamous component is associated with median survival of 7 months to 11 months [4,5].

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5. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin.2021; 71: 209-249.