Pancreas and Biliary Tract

, Haiyan Liu1 and Jun Zhang2



(1)
Department of Laboratory Medicine, Geisinger Health System, Danville, PA, USA

(2)
Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, AZ, USA

 



Keywords
PancreasSerous cystadenomaMucinous cystic neoplasmWith low-Intermediate-Or high-grade dysplasiaIntraductal papillary mucinous neoplasm IPMNs with low-IntermediateOr high-grade dysplasiaIntraductal tubulopapillary neoplasmPancreatic intraepithelial neoplasiaDuctal adenocarcinomaAdenosquamous carcinomaColloid carcinoma (mucinous noncystic carcinoma)Hepatoid carcinomaMedullary carcinomaSignet ring cell carcinomaUndifferentiated carcinomaUndifferentiated carcinoma with osteoclast-like giant cellsAcinar cell carcinomaPancreatoblastomaSolid-pseudopapillary neoplasmNeuroendocrine tumor (NET)Neuroendocrine tumor grade I or grade IINeuroendocrine carcinoma (NEC)Large cell NECSmall cell NECChronic pancreatitisPseudocystAutoimmune pancreatitis (lymphoplasmacytic sclerosing pancreatitis)Lymphoepithelial cystCarcinomaSarcomaLymphomaMetastasisIgG4MaspinpVHLS100PIMP3 (KOC)MUC5ACCK7CK20Cytokeratin 17CEAp53DPC4/SMAD4ClusterinMesothelinMUC1MUC2MUC4MUC6CDX2MLH1MSH2ChromograninSynaptophysinProgesterone receptor (PR)PAX8Glypican-3BCL-10Beta-cateninCD10E-cadherinInhibin-alphaSOX10GATA3TTF1ER



Summary of Pearls and Pitfalls





  • Clinical information such as age, sex, location of a lesion, solid versus cystic, and serum tumor markers, should be taken into consideration.


  • Well-differentiated adenocarcinoma of the pancreas may only show subtle cytological atypia; therefore, variation of nuclear sizes (4:1 ratio), loss of nuclear polarity, and nuclear membrane irregularities are the key criteria to make a diagnosis.


  • Gastrointestinal or mesothelial cell contamination should be excluded before a diagnosis of mucin-producing tumor or well-differentiated adenocarcinoma is rendered.


  • Some pancreatic neuroendocrine neoplasms may show prominent nucleoli and focal significant nuclear atypia, which may mislead one to call it adenocarcinoma or even poorly differentiated carcinoma.


  • Aspirate from an intraductal papillary mucinous neoplasm (IPMN) or mucinous cystic neoplasm (MCN) may contain mainly thick mucinous material and few benign-appearing columnar epithelial cells.


  • Serous cystadenoma may contain only a few groups of benign-appearing epithelial cells in a clear, watery background or bloody background with hemosiderin-laden macrophages; correlation with a radiological finding is important.


  • In addition to pancreatitis, acute inflammatory cells are frequently seen in IPMN, MCN, and high-grade ductal adenocarcinoma .


  • When a markedly cellular specimen with a spectrum from bland to high-grade nuclear atypia is present, a mucin-producing cystic neoplasm, especially an IPMN, should be considered.


  • When a markedly cellular specimen with frankly malignant cells and many single malignant cells and no mucin in the background is present, a metastasis such as a lung or breast primary should be excluded.


  • Cellblock preparation in conjunction with appropriate immunostains is useful in assisting diagnosis of a difficult case.


  • von Hippel gene product (pVHL ), S100P , and maspin are a panel of useful immunomarkers to confirm a diagnosis of well-differentiated adenocarcinoma in cellblock and small tissue core biopsy specimens, but caution should be taken since a mucin-containing cystic neoplasm will demonstrate a similar staining profile. Additionally, gastric contamination will also show positivity for S100P and maspin, and duodenal mucosa will show weakly positive for maspin.


  • Carcinoembryonic antigen (CEA ), mucin (MUC)5 AC, p53 , DPC4/SMAD4 , and insulin-like growth factor 2 mRNA-binding protein 3 (IMP3 )(K homology domain containing protein overexpressed in cancer [KOC]) are also helpful immunomarkers in confirming the diagnosis of adenocarcinoma. Strong immunoreactivity for three of these markers (p53, CEA, IMP3 ) is usually not observed in gastric and duodenal contaminants.


  • Cytokeratin (CK)7 is usually strongly positive in an MCN/IPMN of the pancreas; in contrast, gastric and duodenal mucosal contamination tends to be negative or only very focally positive for CK7 .


  • IPMNs and MCNs are indistinguishable on fine needle aspiration (FNA) samples. This is because the subepithelial ovarian stroma of an MCN is unlikely to be sampled or recognizable on smears or cellblocks.


Common Pancreatic Lesions in the 2010 World Health Organization (WHO) Classification , Modified1





  1. I.


    Epithelial neoplasms


    1. A.


      Exocrine neoplasms


      1. 1.


        Acinar cell cystadenoma

         

      2. 2.


        Microcystic serous cystadenoma

         

      3. 3.


        MCNs, with low-, intermediate-, or high-grade dysplasia

         

      4. 4.


        IPMNs with low-, intermediate, or high-grade dysplasia

         

      5. 5.


        Intraductal tubulopapillary neoplasm

         

      6. 6.


        Pancreatic intraepithelial neoplasia , grade 3 (PanIN-3)

         

      7. 7.


        Invasive ductal adenocarcinoma


        1. (a)


          Tubular adenocarcinoma

           

        2. (b)


          Adenosquamous carcinoma

           

        3. (c)


          Colloid carcinoma (CC, mucinous noncystic carcinoma)

           

        4. (d)


          Hepatoid carcinoma

           

        5. (e)


          Medullary carcinoma

           

        6. (f)


          Signet ring cell carcinoma

           

        7. (g)


          Undifferentiated carcinoma

           

        8. (h)


          Undifferentiated carcinoma with osteoclast-like giant cells

           

         

      8. 8.


        Acinar cell carcinoma

         

      9. 9.


        Mixed carcinoma with two or three components (acinar, neuroendocrine, and ductal)

         

      10. 10.


        Pancreatoblastoma

         

      11. 11.


        Solid-pseudopapillary neoplasm

         

      12. 12.


        Serous cystadenocarcinoma

         

       

    2. B.


      Neuroendocrine neoplasms



      • Neuroendocrine microadenoma (<0.5 cm)


      • Neuroendocrine tumor (NET)



        • Nonfunctional NET, grade I and grade II


        • Functional NET


      • Neuroendocrine carcinoma (NEC )



        • Large cell NEC


        • Small cell NEC

       

     

  2. II.


    Nonneoplastic lesions


    1. A.


      Chronic pancreatitis

       

    2. B.


      Pseudocyst

       

    3. C.


      Autoimmune pancreatitis (lymphoplasmacytic sclerosing pancreatitis)

       

    4. D.


      Lymphoepithelial cyst

       

     

  3. III.


    Metastasis and Rare Lesions

     


Normal Cytology of the Pancreas






  • Normal pancreas consists of a dominant exocrine component and small endocrine component. The exocrine component is composed of approximately 80% acini and a minor component of ductal cells as shown in Fig. 8.1.

    A333337_1_En_8_Fig1_HTML.jpg


    Fig. 8.1
    Histological section of normal pancreatic tissue. H&E stain


  • Acinar cells are present in small, cohesive groups, or singly, and commonly with naked nuclei in the background. The nuclei are eccentrically located, round to ovoid, about the size of a red blood cell, with evenly distributed nuclear chromatin, smooth nuclear contours, and distinct nucleoli. Prominent nucleoli may be present in some acinar cells. The acinar cells usually have well-defined cell borders and moderate to abundant granular cytoplasm. Clear or vacuolated cytoplasm secondary to degeneration may be seen. Normal acinar cells are illustrated in Fig. 8.2.

    A333337_1_En_8_Fig2_HTML.jpg


    Fig. 8.2
    Benign acinar cells . Papanicolaou stain


  • The ductal cells tend to form two-dimensional sheet of variable sizes, with a scant amount of cytoplasm and poorly defined cytoplasmic borders. The cell borders may be prominent, forming an orderly honeycomb appearance. The nuclei are round to ovoid, the same size or slightly large than one red blood cell, with evenly distributed nuclear chromatin, smooth nuclear membranes, and indistinct nucleoli. Figure 8.3 illustrates normal ductal cells .

    A333337_1_En_8_Fig3_HTML.jpg


    Fig. 8.3
    Benign ductal cells . Cohesive, flat sheet of benign ductal cells with small, uniform nuclei and smooth nuclear membranes. Note that folding of the ductal epithelium is present. Papanicolaou stain


  • Islet cells are usually not present or not easily recognizable in fine needle aspiration biopsy (FNAB) smears. They form small, loosely cohesive clusters or may be present singly. The nuclei are small, round, with fine, granular chromatin and small to indistinct nucleoli.


  • Mesothelial cells , endothelial cells, hepatocytes, and small intestinal and gastric glandular cells may be seen in FNAB smears. Benign glandular epithelium with goblet cells and gastric glandular epithelial cells usually seen in an endoscopic ultrasound-guided (EUS)-FNA sample is shown in Fig. 8.4a–h.

    A333337_1_En_8_Fig4a_HTML.jpgA333337_1_En_8_Fig4b_HTML.jpg


    Fig. 8.4
    Benign glandular epithelium with many mucin-containing goblet cells (a, b), gastric foveolar epithelium (c–e), gastric body mucosa (f), and gastric mucosa on cellblock sections (g, h) are frequently present in an EUS-guided FNAB specimen


Chronic Pancreatitis



Key Clinical Features





  • Obstructive jaundice, pain, and weight loss may be present.


Key Radiological Findings





  • A mass lesion or diffuse involvement of the pancreas may be seen radiographically.


Major Cytologic Features





  • Chronic inflammation, acinar atrophy, fibrosis, calcifications, ductal hyperplasia, and relatively increased numbers of islet cells.


  • In the early stage, evidence of acute and chronic inflammation, fat necrosis, and granulation tissue may be the dominant features as shown in Fig. 8.5.

    A333337_1_En_8_Fig5_HTML.jpg


    Fig. 8.5
    Chronic pancreatitis


  • In the late stage, due to an extensive acinar atrophy, the smear may be composed predominately of ductal epithelial cells, fibrosis, chronic inflammatory cells, and islet cells.


  • If the inflammatory component is rich in lymphocytes, plasma cells, and eosinophils, lymphoplasmacytic sclerosing pancreatitis should be suspected.


  • Squamous metaplasia has been described. Ductal epithelial cells associated with significant cytologic atypia may be present.


  • Figure 8.6 shows a sheet of ductal cells with mild-moderate nuclear atypia. The nuclear atypia more frequently shows a combination of nuclear enlargement and prominent nucleoli. In contrast, marked anisonucleosis and/or nuclear membrane irregularity are rare findings .

    A333337_1_En_8_Fig6_HTML.jpg


    Fig. 8.6
    Chronic pancreatitis with mild to moderate nuclear atypia. Diff-Quik stain


Differential Diagnosis





  • Well-differentiated adenocarcinoma


Histology





  • Depending on the stage of chronic pancreatitis, histology may show various degrees of perilobular and intralobular fibrosis, sclerosis, acinar atrophy, ductal proliferation, dilatation, squamous metaplasia, and chronic inflammation to include eosinophils and plasma cells. Langerhans’ islets may show atrophy and distortion; conversely, it may show a marked proliferation of islet cells growing in small cords, clusters, and lobules. Perineurial extension of the proliferative islet cells can be seen, which may simulate a malignant process. An example of a marked proliferation of islet cells in a chronic pancreatitis adjacent to a ductal adenocarcinoma is shown in Fig. 8.7a, b. Immunohistochemical (IHC) stains have demonstrated the presence of all major types of islet cells in a case like this.

    A333337_1_En_8_Fig7_HTML.jpg


    Fig. 8.7
    Marked proliferation of islet cells in a case of chronic pancreatitis which may mimic a malignant process or a pancreatic neuroendocrine tumor


  • In an autoimmune pancreatitis , the infiltrating plasma cells are predominately immunoglobulin G4 (IgG4 )-positive plasma cells. An immunostain for IgG4 may be helpful in diagnosing a difficult case. It should be cautioned, however, that the presence of abundant IgG4-positive plasma cells does not preclude the diagnosis of pancreatic adenocarcinoma because in a small subset of pancreatic adenocarcinoma cases the cancer-adjacent tissue may show features of autoimmune pancreatitis. Examples of autoimmune pancreatitis with many IgG4-positive plasma cells are shown in Fig. 8.8a–c.

    A333337_1_En_8_Fig8_HTML.jpg


    Fig. 8.8
    Autoimmune pancreatitis on smear with groups of mildly atypical ductal cells, fibrous tissue, and inflammatory cells (a), histologic section (b) and many IgG4 -positive plasma cells (c)

Immunohistochemistry



  • Maspin and S100P have been shown to be positive in over 90% of ductal adenocarcinoma s of the pancreas (with nuclear or both nuclear and cytoplasmic staining) and negative in normal ducts and reactive ducts (lack of nuclear staining).


  • Immunostain for pVHL is positive in benign and reactive pancreatic ducts and negative in nearly 100% of ductal adenocarcinoma s.


  • CEA , CK17, and MUC5AC are usually negative in normal and reactive ducts, and the expression of these three markers in ductal adenocarcinoma s was reported as approximately 80%, 60%, and 60%, respectively.


  • Strong and diffuse p53 positivity was reported in approximately 50% of ductal carcinomas and usually negative or only weakly positive in benign/reactive ducts.


  • Clusterin , mesothelin , and prostate stem cell antigen (PSCA) may provide some valuable information. All three markers are much more frequently positive in adenocarcinomas than in reactive ducts .


Well-Differentiated Ductal Adenocarcinoma



Key Clinical Features





  • Epigastric pain radiating to the back, painless jaundice, weight loss, and other general symptoms


  • The average sensitivity of computed tomography (CT)-guided FNAB and EUS-guided FNAB of the pancreas is about 80–90%, and specificity approaches 100%.


  • The main advantages of EUS-guided over CT-guided FNAB are the ability to detect smaller lesions, to identify a possible local invasion of the tumor, and to simultaneously sample the adjacent lymph node for cancer staging .


Key Radiological Findings





  • Hypointense masses on magnetic resonance imaging (MRI) and hypodense masses on CT scans


Major Cytologic Features (Fig. 8.9a, b)





  • Anisonucleosis (variation in nuclear size of greater than a 4:1 ration within an epithelial group)

    A333337_1_En_8_Fig9_HTML.jpg


    Fig. 8.9
    Well-differentiated adenocarcinoma . Nuclear enlargement, nuclear crowding/loss polarity, anisonucleosis, and nuclear membrane irregularities. Papanicolaou stain, ×600


  • Nuclear membrane irregularity


  • Nuclear crowding/overlapping/three-dimensionality


  • Nuclear enlargement (if more than two red blood cells)


Minor Cytologic Features





  • Gap versus confluent cell spacing


  • Hyperchromasia


  • Macronucleoli


  • Mitosis


  • Chromatin clearing


  • Necrosis


  • Single malignant cells


Differential Diagnosis





  • Chronic pancreatitis/autoimmune pancreatitis


  • Acinar cell carcinoma


  • Pancreatic neuroendocrine neoplasm


  • Solid-pseudopapillary neoplasm of the pancreas


  • Metastasis


Histology





  • Haphazardly arranged infiltrating duct-like structures; small, medium-sized, or large duct variant


  • Duct-like structures with angular or irregular contours


  • Desmoplastic stroma with mucin production


  • Perineural and vascular invasion


  • Cytologic bland duct-like structures adjacent to muscular vessels


  • Ruptured and incomplete ducts


  • Single atypical cells

Figure 8.10a–e shows ductal adenocarcinoma with intensive desmoplastic stromal reaction (a), large duct type (b), perineural invasion (c), atypical glands adjacent to muscular vessels (d), and single malignant cells (e).

A333337_1_En_8_Fig10_HTML.jpg


Fig. 8.10
Ductal adenocarcinoma with intensive desmoplastic stromal reaction (a), large-duct type (b), perineural invasion (c), atypical glands adjacent to muscular vessels (d), and single malignant cells (e)

Immunohistochemistry



  • Upregulation of maspin and S100P and downregulation of pVHL have been shown to be the highly sensitive and specific markers for diagnosis of adenocarcinoma of the pancreas. Examples are shown in Fig. 8.11 (double immunostaining of S100P and pVHL) and Fig. 8.12 (double immunostaining of maspin and pVHL).

    A333337_1_En_8_Fig11_HTML.jpg


    Fig. 8.11
    Double immunostaining of pVHL and S100P in a case of adenocarcinoma. Carcinoma is positive for S100P (brown) and normal duct and acinar cells are positive for pVHL (red)


    A333337_1_En_8_Fig12_HTML.jpg


    Fig. 8.12
    Double immunostaining of pVHL and maspin in a case of adenocarcinoma. Carcinoma is positive for maspin (brown) and normal duct and acinar cells are positive for pVHL (red)


  • Expression IMP3 (KOC) has been demonstrated in over 90% of ductal adenocarcinomas; it is negative/very weakly positive in normal ductal epithelium and chronic pancreatitis.


  • SMAD4/DPC4 is negative in 55% of adenocarcinomas.


  • Kirsten rat sarcoma viral oncogene homolog (K-ras) gene mutation was detected in 43–77% of ductal adenocarcinomas of the pancreas in FNAB specimens but was rarely positive in benign conditions.


  • MUC1 has been shown to be positive in the majority of ductal adenocarcinomas and rarely positive in chronic pancreatitis and benign conditions in FNAB specimens.


  • A strong and diffuse expression of claudin 4 protein predominately in a membranous distribution in over 90% of ductal adenocarcinomas of the pancreas, metastatic pancreatic adenocarcinomas, and PanINs. In contrast, most benign ductal epithelium showed focal and weak immunoreactivity.


  • Table 8.1 summarizes the useful IHC markers for the differential diagnosis between pancreatic ductal adenocarcinoma and chronic pancreatitis. Examples of staining for other IHC markers are shown in Fig. 8.13a–d: a (IMP3 ), b (DPC4/SMAD4 ), c (p53 ), and d (MUC5AC ) .

    A333337_1_En_8_Fig13_HTML.jpg


    Fig. 8.13
    Other useful immunohistochemical markers in ductal adenocarcinoma such as IMP3 (a), loss of DPC4/SMAD4 (b), monoclonalCEA (c), and MUC5AC (d)



    Table 8.1
    Useful immunomarkers for differential diagnosis between pancreatic ductal adenocarcinoma and chronic pancreatitis








































    Markers
    Adenocarcinoma
    Chronic pancreatitis

    pVHL

    Negative
    Positive

    Maspin

    >90% positive
    Negative

    S100P

    >90% positive
    Negative or cytoplasmic staining

    IMP3

    >80% positive
    Negative

    MUC5AC

    60% positive
    Negative

    P53
    50% diffusely and strongly positive
    Weak or negative

    DPC4/SMAD4

    50% loss
    Positive


Treatment and Prognosis





  • 5-year survival rate is less than 5%. Most patients die within 1 year following the diagnosis.


Moderately and Poorly Differentiated Adenocarcinoma






  • In general, a diagnosis of moderately and poorly differentiated adenocarcinoma tends to be straightforward on both FNA and tissue biopsy specimens.


  • Abnormal cytologic features are more pronounced than in well-differentiated adenocarcinoma.


  • In addition to marked nuclear pleomorphism and nuclear membrane irregularities, single malignant cells, tumor necrosis, mitoses, and prominent nucleoli are frequently present. Figure 8.14a, b show examples of moderately and poorly differentiated adenocarcinoma, respectively .

    A333337_1_En_8_Fig14_HTML.jpg


    Fig. 8.14
    Moderately differentiated adenocarcinoma (a) and poorly differentiated adenocarcinoma (b). Papanicolaou stain


Adenosquamous Carcinoma






  • Adenosquamous carcinoma accounts for approximately 1–4% of all exocrine malignant tumors of the pancreas.


  • Pure squamous cell carcinoma of the pancreas is very rare. A metastasis such as from the lung should be excluded first.


  • An FNAB smear generally shows moderate to high cellularity with a dual population of malignant squamous and glandular epithelial cells.


  • Tumor necrosis frequently presents. Rare cytoplasmic vacuoles may be the only evidence of glandular differentiation. Keratin pearls may be present. Keratinization may be absent; instead, the tumor cells display dense cytoplasm. Sometimes malignant squamous cells become a predominant cell population.


  • However, careful search may find signet ringlike glandular cells. Figure 8.15a, b reveal some characteristic cytologic features of adenosquamous carcinoma .

    A333337_1_En_8_Fig15_HTML.jpg


    Fig. 8.15
    Adenosquamous carcinoma . Intracytoplasmic mucin vacuoles in (a) and malignant keratinizing squamous cells in (b). Papanicolaou stain, ×600


Histology





  • Histologically, it shows both gland-forming adenocarcinoma with intracellular/extracellular mucin and squamous differentiation of prominent intercellular junctions and varying degrees of keratinization.


  • Immunohistochemically, a tumor is frequently negative for p16 and SMAD4/DPC4 with strong p53 expression.


  • Most cases show K-ras mutation at codon 12 .


Colloid Carcinoma (CC )






  • CC, mucinous noncystic carcinoma, characterized by stromal mucinous nodules containing scant malignant epithelial cells that is morphologically similar to CC of the breast and skin, had been previously regarded as a histologic variant of ductal adenocarcinoma as shown in Fig. 8.16a, b.

    A333337_1_En_8_Fig16_HTML.jpg


    Fig. 8.16
    (a, b) Colloid carcinoma with groups of atypical epithelial cells in the background of thick mucin


  • Mean age of CC is 61 without gender predominance.


  • The average size of the tumor at the time of diagnosis is 6.0 cm.


  • Approximately half of the cases are associated with an IPMN, intestinal type.


  • Studies of molecular phenotypes of CC show expression of MUC2 and lack of mutation of K-ras gene. In contrast, ductal adenocarcinoma of the pancreas is usually positive for MUC1 and associated with k-ras gene mutation in codon 12. See Fig. 8.17a, b.

    A333337_1_En_8_Fig17_HTML.jpg


    Fig. 8.17
    (a, b) Histological section of colloid carcinoma (a) and tumor cells are positive for MUC2 (B) which is usually negative in ductal/tubular adenocarcinoma


  • More recently, Caudal type homeobox 2 (CDX2 ) is much more frequently positive in CC than in ductal adenocarcinoma . Conversely, galactin 3 displayed a strong positivity in the majority of ductal adenocarcinoma but only positive in 15–20% of CC.


  • Most importantly, the clinical course of CC appears to be significantly better than that of conventional ductal adenocarcinoma of the pancreas, with a 5-year survival rate of 55% in CC vs. 5% in ductal adenocarcinoma of the pancreas .


Other Variants of Ductal Carcinoma






  • These include medullary carcinoma, hepatoid carcinoma , undifferentiated (anaplastic) carcinoma, signet ring cell carcinoma , and mixed ductal-endocrine carcinoma.


  • An example of medullary carcinoma of the pancreas is shown in Figs. 8.18a, b and 8.19a, b. Medullary carcinoma of the pancreas has a similar morphology to medullary carcinoma of the colon and other organs characterized by poor differentiation with limited gland formation, syncytial growth pattern, and pushing growth border with lymphoid infiltration. Most medullary carcinomas are microsatellite unstable (MSI +) and wild type for K-ras gene. Immunostains demonstrate loss of one or two of the mismatch repair (MMR) proteins (MutL homolog 1 [MLH1 ], postmeiotic segregation increased 2 [PMS2], MutS protein homolog 2 [MSH2 ], and MutS protein homolog 6 [MSH6]). Despite poor differentiation, the prognosis for patients with a medullary carcinoma is better than ductal adenocarcinoma .

    A333337_1_En_8_Fig18_HTML.jpg


    Fig. 8.18
    (a, b) Medullary carcinoma with large tumor cells singly or in small clusters in the background of numerous lymphoid cells


    A333337_1_En_8_Fig19_HTML.jpg


    Fig. 8.19
    Histological section of medullary carcinoma (a) and immunostain showing loss of MSH2 expression on tumor cells with positive internal control (b)


Pancreatic Neuroendocrine Neoplasms



Key Clinical Features





  • Pancreatic neuroendocrine neoplasms are relatively rare tumors, accounting for less than 5% of all pancreatic neoplasms.


  • The neoplasms frequently occur in adults and rarely in children.


  • The majority of pancreatic neuroendocrine neoplasms are functional. Nonfunctional tumors account for 15–30% of reported cases.


  • In the new WHO classification (2010), pancreatic neuroendocrine neoplasms encompass a spectrum of lesions, including microadenoma (<0.5 cm); NET, grade I, and grade II; and NEC , large cell NEC and small cell NEC . The proposed grading is based on counting mitoses or Ki-67 index as summarized in Table 8.2. The grading system requires mitotic count in at least 50 high-power fields (HPFs) and Ki67 index using the MIB antibody as a percentage of 500–2000 tumor cells counted in the areas of strongest nuclear labelling. If a grade differs for mitotic count compared with Ki67 index, it is suggested the higher grade be assumed.


    Table 8.2
    Pancreatic neuroendocrine neoplasms classified based on mitotic rates and Ki67 proliferative index
























    Grade
    Mitotic count
    Ki67 index

    NET, grade 1
    < 2/per 10 HPF
    ≤ 2% Ki67 index

    NET, grade 2
    2–20/per 10 HPF
    3–20% Ki67 index

    NEC, grade 3
    >20/per 10 HPF
    >20% Ki67 index


  • Caution should be taken in grading a NET on a cellblock preparation or a small tissue biopsy specimen. An accurate grading can be even more challenging in the presence of a large amount of lymphoid cells/inflammatory cells.


  • Our experience shows that most NECs, especially small cell carcinomas, have a greater than 50% Ki67 index. Caution should be taken when dealing with a small cell carcinoma/high-grade NEC with a Ki67 index marginally over 20% on cytologic specimens .


Key Radiological Findings





  • CT scans reveal solid, circumscribed, enhanced masses. Cystic change and calcification may occur.


Major Cytologic Findings





  • Hypercellular smears with a mixture of loosely cohesive clusters and single cells as shown in Figs. 8.20a, b and 8.21a–c. Acinar-like formation, perivascular tumor growth, or trabecular pattern can be seen.

    A333337_1_En_8_Fig20_HTML.jpg


    Fig. 8.20
    (a, b) Pancreatic endocrine neoplasm . Loosely cohesive clusters and single cells with salt-pepper nuclear chromatin pattern, abundant cytoplasm, and plasmacytoid appearance. Papanicolaou stain


    A333337_1_En_8_Fig21_HTML.jpg


    Fig. 8.21
    Pancreatic neuroendocrine tumor with prominent cytoplasmic vacuoles and prominent nucleoli in some tumor cells (a, b) and on cellblock section (c)


  • The neoplastic cells are typically monotonous, with focal nuclear pleomorphism. Individual cells with well-defined cytoplasm or even plasmacytoid appearance are common findings.


  • The nuclei tend to be round to ovoid with smooth nuclear membrane and salt-and-pepper nuclear chromatin pattern. Binucleated and multinucleated neoplastic cells are usually seen.


  • In less differentiated tumors, predominant single cells with high nuclear-to-cytoplasmic ratio, prominent nucleoli, and mitoses are characteristic features.


  • Pancreatic NEC is relatively rare and shows cytologic features similar to high-grade NECs in other organs .


Differential Diagnosis





  • Acinar cell carcinoma


  • Ductal adenocarcinoma


  • Solid-pseudopapillary tumor (SPT)


  • Islet cell hyperplasia


Histology





  • Various histologic patterns such as nesting, trabecular, glandular, gyriform, tubuloacinar, and pseudorosette arrangements.


  • Granular amphophilic to eosinophilic granular cytoplasm, but can be clear, lipid-rich, oncocytic, or have “rhabdoid” features.


  • Salt-and-pepper nuclear chromatin frequently with distinct or even prominent nucleolus.


  • Foci of nuclear pleomorphism can be seen.


  • Tumor necrosis is infrequent and often limited.


  • Amyloid deposition and calcification can be present.


  • In NEC , prominent nuclear atypia, necrosis, a high Ki67 index (>20%), and >20/10 HPFs mitotic rates. Primary small cell carcinoma of the pancreas can be positive for thyroid transcription factor 1 (TTF1 ).


  • Figure 8.22a, b highlights a lipid-rich variant .

    A333337_1_En_8_Fig22_HTML.jpg


    Fig. 8.22
    Lipid-rich variant of neuroendocrine tumor (a) and positive for chromogranin (b)

Immunohistochemistry



  • Positive for chromogranin (over 90%) and synaptophysin (100%).


  • Cluster of differentiation (CD)56 is the most sensitive neuroendocrine marker for lung small cell carcinoma, which is only positive in approximately 60% of pancreatic NETs.


  • CK7 and CK20 are frequently negative.


  • Positive for progesterone receptors (PR , 60%), paired box gene (PAX)8 (60%, polyclonal antibody), islet-1(82%), and pancreas/duodenum homeobox-1 (PDX-1, 72%). None of these markers is entirely specific for a pancreatic NET.


  • An example of pancreatic NET positive for PR , PAX8 , and islet-1 is shown in Fig. 8.23a–d.

    A333337_1_En_8_Fig23_HTML.jpg


    Fig. 8.23
    An example of pancreatic neuroendocrine tumor on H&E section (a), positive for PR (b), PAX8 (c), and islet-1 (d)


Indication of Malignancy





  • Reliable histological criteria, as well as cytologic criteria, to predict the malignant potential are not available.


  • Tumor necrosis is a good indicator for malignancy. The unequivocal indicators for malignancy are metastasis and invasion of adjacent organs.


  • Quantitative fluorescence in situ hybridization (FISH) technique indicates that telomere shortening is a feature of malignant tumor.


  • The term neuroendocrine carcinoma is reserved for small cell carcinoma or large NEC only .


Treatment and Prognosis





  • Depends on the clinical behavior of the tumor


Acinar Cell Carcinoma



Key Clinical Features



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Jan 30, 2018 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Pancreas and Biliary Tract

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