Research ArticleCancer

A multimodality test to guide the management of patients with a pancreatic cyst

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Science Translational Medicine  17 Jul 2019:
Vol. 11, Issue 501, eaav4772
DOI: 10.1126/scitranslmed.aav4772
  • Fig. 1 Clinical features of all of the patients with pancreatic cysts.

    This heatmap shows the clinical features of the 862 patients with pancreatic cysts. Areas highlighted in black show the features present in the different types of cysts. For example, one can easily see that almost all the patients with MCNs were female, with cysts located in the body or tail of the pancreas. MPD, main pancreatic duct; PDAC, pancreatic ductal adenocarcinoma; MCN, mucinous cystic neoplasm; PanNET, pancreatic neuroendocrine tumor; SCN, serous cystic neoplasm; SPN, solid pseudopapillary neoplasm.

  • Fig. 2 Molecular features of all of the pancreatic cysts.

    This heatmap shows the molecular features of the 862 patients with pancreatic cysts. Areas highlighted in black show the features present in the different types of cysts. For example, one can see that GNAS mutations occur almost exclusively in patients with IPMN and PDAC and that they occur in cysts with all grades of dysplasia. In contrast, SMAD4 mutations occur far more commonly in patients with PDAC or IPMNs with cancer or high-grade dysplasia than in patients with low- or intermediate-grade dysplasia.

  • Fig. 3 Clinical management of patients with pancreatic cysts.

    This figure shows how the type of pancreatic cyst determines the risk of the cyst developing cancer, which in turn dictates clinical management. Serous cystic neoplasms and pseudocysts have essentially no malignant potential and therefore require no monitoring. In contrast, cystic degeneration of a PDAC, PanNET, or solid pseudopapillary neoplasm are, or have a high risk for becoming, malignant, and therefore should undergo surgical resection. IPMNs and MCNs are mucin-producing cysts. A small number of these harbor high-grade dysplasia or cancer and should be surgically resected, while the remaining mucin-producing cysts simply need surveillance.

  • Fig. 4 Management of pancreatic cysts.

    These donut charts show the management recommendations based on CompCyst and standard of care compared with the gold standard, pathology. The center of the circle indicates the management recommendation based on the final surgical pathology classification. A fully solid circle—one where the inner and outer circles are fully the same color—would indicate 100% accuracy. The performance of CompCyst compared with surgical pathology for cysts in whom the correct management was discharge, monitoring, or surgery is shown in (A), (B), or (C), respectively. The performance of standard of care compared with surgical pathology is shown in (D), (E), or (F), respectively.

  • Fig. 5 Classification of the type of pancreatic cyst.

    These two heatmaps compare the CompCyst classification (A) and physician’s preoperative diagnosis based on clinical and imaging features (B) with surgical pathology for classifying the type of pancreatic cyst. The fraction of cysts classified to be of the indicated type is shown in the color bar.

  • Table 1 General demographics and imaging features for all 862 patients with surgically resected pancreatic cysts.

    IQR, interquartile range; N/A, not applicable.

    All cysts
    (n = 862)
    Nonmalignant cysts (n = 148)Cysts with malignant
    potential (n = 600)
    Malignant cysts (n = 114)
    Benign
    other*
    (n = 11)
    Pseudocyst
    (n = 22)
    Serous
    cystic
    neoplasms
    (n = 115)
    Mucin-
    producing
    cysts
    (n = 600)
    Mucinous
    cystic
    neoplasm
    (n = 153)
    IPMN
    (n = 447)
    Pancreatic
    adenocarcinoma
    (n = 62)
    Pancreatic
    neuroendocrine
    tumor (n = 29)
    Solid
    pseudopapillary
    tumor (n = 23)
    Age at surgery,
    median (IQR)
    64
    (52–72)
    56
    (50–76)
    53.5 (45–61)57 (44–67)66 (54–73)47 (37–57)69
    (63–74)
    72 (65–78)61 (50–71)28 (23–42)
    Gender
    Female, no. (%)560 (65)8 (73)13 (59)86 (75)386 (64)151 (99)235 (53)31 (50)14 (49)22 (96)
    Missing data,
    no. (%)
    0000000000
    Racial category
    Caucasian, no. (%)681 (79)8 (73)16 (73)81 (70)476 (79)124 (81)352 (79)56 (90)27 (93)17 (74)
    Asian, no. (%)107 (12)1 (9)018 (16)81 (13)10 (7)71 (16)3 (5)04 (17)
    African American,
    no. (%)
    41 (5)1 (9)5 (23)7 (6)22 (4)8 (5)14 (3)2 (3)2 (7)2 (9)
    Other, no. (%)17 (2)006 (5)10 (2)5 (3)5 (1)1 (2)00
    Missing data,
    no. (%)
    16 (2)1 (9)1 (4)3 (3)11 (2)6 (4)5 (1)000
    Symptoms
    Present, no. (%)335 (39)2 (18)15 (68)34 (30)227 (38)67 (44)160 (36)42 (68)7 (24)8 (35)
    Nonspecific
    abdominal
    pain, no. (%)
    251 (75)1 (50)15 (100)30 (88)175 (77)63 (94)112 (70)18 (43)4 (57)8 (35)
    Pancreatic
    abdominal
    pain, no. (%)
    167 (50)1 (50)10 (67)13 (38)126 (56)35 (52)92 (58)11 (26)2 (29)3 (13)
    Acute
    pancreatitis,
    no. (%)
    78 (23)1 (50)9 (60)2 (6)64 (28)12 (18)52 (33)1 (2)01 (4)
    Chronic
    pancreatitis,
    no. (%)
    29 (8)1 (50)4 (27)1 (3)21 (9)3 (4)18 (11)2 (4)00
    Jaundice, no. (%)31 (9)002 (6)15 (6)015 (9)13 (31)01 (4)
    Weight loss,
    no. (%)
    140 (42)2 (100)8 (53)8 (24)85 (4)15 (22)70 (45)30 (71)5 (71)2 (9)
    Missing data,
    no. (%)
    12 (1)00012 (2)3 (2)9 (2)000
    No. of cysts
    Multiple, no. (%)254 (30)2 (18)5 (23)20 (17)197 (33)12 (8)185 (41)21 (34)8 (28)1 (4)
    Missing data,
    no. (%)
    27 (3)002 (2)21 (4)5 (3)16 (4)2 (3)02 (9)
    Cyst size cm,
    median (IQR)§
    3.5
    (2.5–5.2)
    3.7
    (3.1–4.7)
    4.5 (3.3–6.3)4.6 (3.2–7.5)3.5 (2.6–5.2)4.3
    (3.1–7.0)
    3.3
    (2.3–4.0)
    3.9 (2.2–5.1)2.2 (2.0–3.2)5.2 (3.5–9.0)
    Missing data,
    no. (%)
    34 (4)3.7
    (3.1–4.7)
    1 (5)2 (2)27 (5)4 (3)23 (5)3 (5)01 (4)
    Location
    Head/uncinate,
    no. (%)
    352 (41)4 (36)8 (36)37 (32)258 (43)1 (1)257 (57)32 (52)5 (17)8 (35)
    Neck, no. (%)12 (1)005 (4)5 (1)1 (1)4 (1)01 (4)1 (4)
    Body/tail, no. (%)485 (56)7 (64)14 (64)73 (63)324 (54)149 (97)175 (39)30 (48)23 (79)14 (61)
    Whole gland,
    no. (%)
    8 (1)0008 (1)08 (2)000
    Missing data,
    no. (%)
    5 (1)0005 (1)2 (1)3 (1)000
    Mural nodule/solid component
    Present, no. (%)287 (33)4 (36)7 (32)25 (22)182 (3)42 (28)140 (31)37 (60)13 (45)19 (83)
    Missing data,
    no. (%)
    45 (5)01 (4)6 (5)32 (5)8 (5)24 (6)2 (3)04 (17)
    Communication with main pancreatic duct
    Present, no. (%)267 (31)2 (18)1 (4)21 (18)223 (37)8 (5)215 (48)15 (24)4 (14)1 (4)
    Absent, no. (%)250 (29)6 (55)9 (41)45 (39)14869 (45)79 (18)12 (19)16 (55)14 (61)
    Unclear, no. (%)279 (32)3 (27)7 (32)42 (37)18263 (41)119 (27)31 (50)9 (31)5 (22)
    Missing data,
    no. (%)
    66 (8)05 (23)7 (6)47 (8)13 (9)34 (7)4 (7)03 (13)
    Type of IPMN
    Main or
    mixed-duct
    IPMN
    N/AN/AN/AN/AN/AN/A165 (37)N/AN/AN/A
    Branch-duct IPMNN/AN/AN/AN/AN/AN/A177 (40)N/AN/AN/A
    Missing data,
    no. (%)
    N/AN/AN/AN/AN/AN/A105 (23)N/AN/AN/A
    Dilated main pancreatic duct (mm)
    5 to 9 mm no. (%)144 (13)1 (9)3 (13)10 (9)115 (19)2 (1)113 (25)13 (21)2 (7)0
    ≥10, no. (%)100 (12)01 (5)3 (3)80 (13)2 (1)78 (17)14 (23)2 (7)0
    Missing data,
    no. (%)
    165 (19)1 (9)1 (5)16 (14)126 (21)21 (14)105 (24)9 (14)1 (3)11 (48)

    *Includes seven retention cysts, two lymphoepithelial cysts, one simple mucinous cyst, and one duplication cyst.

    †Includes one intraductal tubulopapillary neoplasm.

    ‡Acute pancreatitis within the last year.

    §If more than one cyst largest cyst size noted.

    ‖Based on evaluation of preoperative imaging data.

    ¶Defined as communication between the main pancreatic duct and the cyst on any imaging.

    • Table 2 Frequency of molecular features in different types of pancreatic cyst.

      All cysts
      (n = 862)
      Nonmucinous cysts (n = 148)Mucinous cysts (n = 600)Malignant cysts (n = 114)
      Retention
      cyst (n = 7)
      Other
      nonmalignant
      cysts (n = 26)*
      Serous
      cysts
      (n = 115)
      Mucin-
      producing
      cysts (600)
      Mucinous
      cystic
      neoplasm
      (n = 153)
      IPMN
      (n = 447)
      Pancreatic
      adenocarcinoma
      (n = 62)
      Pancreatic
      neuroendocrine
      tumor (n = 29)
      Solid
      pseudopapillary
      tumor (n = 23)
      Mutations
      KRAS, no. (%)451 (52)3 (43)2 (8)0390 (65)53 (35)337 (76)53 (85)2 (7)1 (4)
      GNAS, no. (%)260 (30)000252 (42)3 (2)249 (56)8 (13)00
      KRAS or GNAS,
      no. (%)
      502 (58)3 (43)2 (8)0440 (73)56 (37)384 (86)54 (87)2 (7)1 (4)
      RNF43, no. (%)213 (25)1 (14)02 (2)192 (32)20 (13)172 (39)15 (24)03 (13)
      CDKN2A, no. (%)47 (5)1 (14)0036 (6)8 (5)28 (6)10 (16)00
      CTNNB1, no. (%)50 (6)01 (5)1 (1)27 (5)2 (1)25 (6)1 (2)020 (87)
      SMAD4, no. (%)50 (6)003 (3)26 (4)2 (1)24 (5)21 (34)00
      TP53, no. (%)151 (18)1 (14)02 (2)95 (16)13 (8)83 (19)46 (74)1 (3)5 (22)
      VHL, no. (%)55 (6)1 (14)049 (43)5 (1)05 (1)000
      BRAF - no. (%)14 (2)00012 (2)4 (3)8 (2)2 (3)00
      NRAS, no. (%)4 (0)001 (1)3 (1)03 (1)000
      PIK3CA, no. (%)24 (3)00019 (3)1 (1)18 (4)3 (5)02 (9)
      Missing data,
      no. (%)
      0000000000
      Loss of heterozygosity
      LOH chr3 (VHL),
      no. (%)
      61 (7)01 (5)30 (26)24 (4)1 (1)23 (5)4 (6)2 (7)0
      LOH chr9
      (CDKN2A),
      no. (%)
      42 (5)1 (14)01 (1)21 (4)2 (1)19 (4)13 (21)6 (21)0
      LOH chr17
      (RNF43),
      no. (%)
      49 (6)002 (2)38 (6)5 (3)33 (7)6 (10)3 (10)0
      LOH chr17
      (TP53), no. (%)
      41 (5)00024 (4)2 (1)22 (5)17 (27)00
      LOH chr18
      (SMAD4), no. (%)
      48 (6)002 (2)27 (5)1 (1)26 (6)13 (21)6 (21)0
      VHL or LOH chr3
      (VHL), no. (%)
      102 (12)1 (14)1 (5)65 (59)29 (5)1 (1)28 (6)4 (6)2 (7)0
      Missing, no. (%)000000000
      Aneuploidy
      COUNT_GL_Z
      score 3
      (Range)
      104 (12)1.4 (0–3)1.8 (0–17)3.5
      (−1–34)
      1.0 (0–16)5.2 (0–37)8.9 (0–33)01.5 (0–6)
      Missing data,
      no. (%)
      0000000000
      Protein data
      CEA
      >192 ng/ml,
      no. (%)
      237 (27)1 (14)3 (12)3 (2)201 (30)70 (46)131 (29)28 (45)1 (3)0
      ≤192 ng/ml,
      no. (%)
      548 (64)3 (43)12 (46)94 (82)220 (37)58 (38)162 (36)21 (34)26 (90)17 (74)
      Missing data,
      no. (%)
      77 (9)3 (43)11 (42)18 (16)178 (30)25 (16)154 (34)13 (21)2 (7)6 (26)
      VEGF-A
      >5000 pg/ml,
      no. (%)
      60 (7)0033 (29)20 (3)3 (2)17 (4)5 (8)2 (7)0
      ≤5000 pg./ml,
      no. (%)
      725 (84)7 (100)26 (100)74 (64)515 (86)145 (95)370 (83)57 (92)27 (93)19 (83)
      Missing data,
      no. (%)
      77 (9)008 (7)65 (11)5 (3)60 (13)004 (17)

      *Includes simple mucinous cysts (n = 1), lymphoepithelial cyst, (n = 2), duplication cyst (n = 1), and pseudocyst (n = 22).

      †Includes one intraductal tubulopapillary neoplasm.

      Supplementary Materials

      • stm.sciencemag.org/cgi/content/full/11/501/eaav4772/DC1

        Fig. S1. Classification of patients into management groups.

        Fig. S2. Cyst fluid VEGF-A.

        Fig. S3. Cyst fluid CEA.

        Fig. S4. Association between aneuploidy and high-grade dysplasia or cancer.

        Table S1. Clinical, imaging, molecular, and pathological data for all 862 patients with surgically resected pancreatic cysts.

        Table S2. Genetic characteristics of the IPMNs based on histological subtype.

        Table S3. CompCyst and the preoperative clinical diagnosis and management recommendations.

        Table S4. Performance of the three-step approach to classify cysts into management groups.

        Table S5. CompCyst and preoperative clinical management recommendations compared with surgical pathology.

        Table S6. Identification of cyst type: comparison of CompCyst, the preoperative clinical diagnosis, and surgical pathology.

        Table S7. Primer sequences used in Safe-SeqS.

        Table S8. Primer sequences used in Safe-SeqS for loss of heterozygosity.

        Table S9. Frequency of molecular features associated with different grades of dysplasia in mucin-producing cysts.

      • The PDF file includes:

        • Fig. S1. Classification of patients into management groups.
        • Fig. S2. Cyst fluid VEGF-A.
        • Fig. S3. Cyst fluid CEA.
        • Fig. S4. Association between aneuploidy and high-grade dysplasia or cancer.
        • Legends for tables S1 to S9

        [Download PDF]

        Other Supplementary Material for this manuscript includes the following:

        • Table S1 (Microsoft Excel format). Clinical, imaging, molecular, and pathological data for all 862 patients with surgically resected pancreatic cysts.
        • Table S2 (Microsoft Excel format). Genetic characteristics of the IPMNs based on histological subtype.
        • Table S3 (Microsoft Excel format). CompCyst and the preoperative clinical diagnosis and management recommendations.
        • Table S4 (Microsoft Excel format). Performance of the three-step approach to classify cysts into management groups.
        • Table S5 (Microsoft Excel format). CompCyst and preoperative clinical management recommendations compared with surgical pathology.
        • Table S6 (Microsoft Excel format). Identification of cyst type: comparison of CompCyst, the preoperative clinical diagnosis, and surgical pathology.
        • Table S7 (Microsoft Excel format). Primer sequences used in Safe-SeqS.
        • Table S8 (Microsoft Excel format). Primer sequences used in Safe-SeqS for loss of heterozygosity.
        • Table S9 (Microsoft Excel format). Frequency of molecular features associated with different grades of dysplasia in mucin-producing cysts.

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