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`islet Cell Tumors of the Pancreas:
`Pathologic—Imaging Correlation Among
`Size, Necrosis and Cysts, Calcification,
`Malignant Behavior, and Functional Status
`
`
`
`OBJECTIVE. The purposeof our study wasto correlate the imaging and pathologic
`features of islet cell tumors with regard to tumor size, necrosis and cysts, calcifica-
`tion, malignant behavior, and functional status.
`MATERIALS AND METHODS.Weretrospectively reviewed the clinical, pathologic, and
`imaging features of all 133 cases of pathologically proved islet cell tumors of the pancreas
`seen at the Armed Forces Institute of Pathology. Clinical data, including the patients’ symp-
`toms and serologic characteristics, were used to distinguish hyperfunctioning tumors
`(those causing symptomsrelated to elevated serum polypeptide levels) from nonhyper-
`functioning tumors; hyperfunctioning tumors were divided further into insulin-producing
`and non-insulin-producing types. All patients had at least one cross-sectional imaging
`study, including CT (n = 118), sonography (n = 42), or MR imaging (n = 22). Clinical, patho-
`logic, and imaging features were evaluated and correlated with tumor size, necrosis and
`cysts, calcification, local invasion, vascular invasion, metastases, and functional status.
`RESULTS.Islet cell tumors with areas of necrosis or cystic change found patholog-
`ically and on imaging studies (56/133) were larger (8.4 cm in mean transverse diame-
`ter) than homogeneoussolid lesions (2.9 cm in mean transverse diameter) and were
`predominantly non-insulin producing (48/56) and nonhyperfunctioning (36/56). Of the
`43 insulinomas, 35 were small (2.2 cm in mean transverse diameter), solid, and homo-
`geneous. Larger size also was associated with calcification and malignant behavior,
`including local invasion, vascular invasion, and distant metastases.
`CONCLUSION.Our findings show that cystic and necrotic islet cell tumors are usu-
`ally non-insulin-producing and nonhyperfunctioning neoplasms and larger than the
`typically solid and small insulinomas. Calcification, local invasion, vascular invasion,
`and metastatic disease are more commonly seen with larger neoplasms.
`
`AJR 1995; 165:1175-1179
`
`Islet cell tumors constitute a broad group of endocrine neoplasms. They are
`best divided on clinical groundsinto those that are hyperfunctioning (the so-called
`functioning islet cell tumors) and those that are nonhyperfunctioning (the so-called
`nonfunctioning islet cell tumors). One would expect hyperfunctioning tumors to be
`manifested earlier and to be small
`in comparison with nonhyperfunctioning
`tumors, which one would expect to be manifested later by virtue of masseffect,
`local invasion, or metastases. Furthermore, one would expect larger tumors to
`have areas of necrosis or cystic degeneration. We studied the imaging and patho-
`logic features of 133 cases and correlated the findings of size, necrosis and cysts,
`calcification, malignant behavior, and functional status of the islet cell tumors.
`
`Materials and Methods
`
`Weretrospectively reviewed the clinical records, radiologic appearance, and pathologic
`findings of all 133 islet cell tumors studied by cross-sectional imaging at the Armed Forces
`Institute of Pathology between January 1980 and January 1994. These tumors occurred in
`124 patients; multiple tumors were found in seven patients. All cases were pathologically
`proved by surgical resection or surgical inspection and by biopsy results. Results of immuno-
`histochemical staining performed to determine specific hormone production within each tumor
`varied from case to case. A single case of nesidioblastosis was excluded from the study.
`
`West-Ward Pharm.
`Exhibit 1007
`Page 001
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`Peter C. Buetow! 2
`Tremont V. Parrino2:?
`James L. Buck!2
`Linda Pantongrag-Brown'2
`Pablo R. Ros'4
`Abraham H. Dachman™>
`David F. Cruess®
`
`Received March 22, 1995; acceptedafter revi-
`sion June 15, 1995.
`
`The opinions and assertions contained herein
`are the private views of the authors and are not to
`be construed asofficial or as reflecting the viewsof
`the Departments of Defense, Army, or Navy.
`Presented at the annual meeting of the Ameri-
`can Roentgen Ray Society, Washington, DC, April—
`May 1995.
`‘Departmentof Radiologic Pathology, Armed Forc-
`es Institute of Pathology, Bldg. 54, Rm. M-121, Alaska
`Ave. and Fem St, N.W., Washington, DC 20306-
`6000. Address correspondence to P. C. Buetow.
`2Departments of Radiology and Nuclear Medi-
`cine, Uniformed Services University of the Health
`Sciences, Bethesda, MD 20814-4799.
`3Departmentof Radiology, National Naval Med-
`ical Center, Bethesda, MD 20814-4799.
`4 Departmentof Radiology, University of Florida,
`Gainesville, FL 32610.
`
`5 Departmentof Radiology, University of Chicago,
`Chicago,IL 60637.
`SDepartment of Preventive Medicine, Uni-
`formed Services University of the Health Sciences,
`Bethesda, MD 20814-4799.
`0361-803X/95/1655-1175
`© American Roentgen Ray Society
`
`West-Ward Pharm.
`Exhibit 1007
`Page 001
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`BUETOW ETAL.
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`AJR:165, November 1995
`
`Clinical data regarding the patients’ presenting signs and symptoms
`were recorded. Criteria used to diagnose functioning islet cell tumors
`were asfollows: insulinoma—symptomatic hypoglycemia with inappropri-
`ately elevated plasmainsulin levels; gastrinoma—symptomsandsignsof
`peptic ulcer disease and elevated serum gastrin levels; glucagonoma—
`diabetes mellitus, dermatitis, and painful glossitis; somatostatinoma—ele-
`vated serum somatostatin levels, diabetes mellitus, gallbladder disease,
`and steatorrhea; vipoma—profuse secretory diarrhea and elevated vaso-
`active intestinal polypeptide levels; and adrenocorticotropin hormone
`(ACTH)-producing
`tumors—Cushing’s
`syndrome. Tumors
`causing
`slightly elevated serum peptide levels or positive immunohistochemical
`staining results but not causing symptoms were classified as nonhyper-
`functioning tumors. Tumors causing elevated pancreatic polypeptide lev-
`els also were classified as nonhyperfunctioning tumors. Three patients
`with type 1 multiple endocrine neoplasia syndrome had gastrinomas.
`One hundred eighteen patients had CT, 42 had sonography, and 22
`had MR imaging. Imaging features were analyzed independently by two
`tadiologists and were correlated with pathologic and surgical findings.
`These featuresincluded the size and location of the mass; the presence
`of cystic changes;findings of local invasion into surrounding organs or
`adenopathy; vascular invasion into the splenic vein, superior mesenteric
`vein, or splenic artery; and the presence of metastatic disease involving
`the liver or other distant organs. MR imaging and CTfindings also were
`used to identify solid nonenhancing areas and solid homogeneously
`enhancing masses. CT alone was used to detect the presence of calcifi-
`cation. Any discrepancies were resolved by consensus. With regard to
`location,
`in two cases in which the lesions were extremely large and
`
`replaced the entire pancreas, the center was recorded as being within
`the body of the pancreas. Imaging studies were performed on a wide
`variety of equipment over many years, and protocols regarding imaging
`parameters, contrast injections, and other details were not standardized.
`Correlation was made among the description and photographs of the
`gross specimen, the histopathologic findings, and the internal morphology
`on imaging studies. Tumors were classified as solid homogeneous
`masses when no necrosis or cystic change was seen pathologically and
`whena uniform solid tumor was identified by CT, sonography, or MR imag-
`ing. All the remaining tumors were classified as heterogeneous and as
`having areas of necrosis; some of these tumors were classified further as
`cystic. Tumors were classified as cystic when fluid-filled or empty cavities
`were seen pathologically and were correlated with areas of water density
`on CT scans, anechoic areas with acoustic enhancement on sonograms,
`or areas of watersignal intensity on T1- and T2-weighted MR images. Cor-
`relation also was made between the imaging and pathologic findings for
`the clinically hyperfunctioning tumors (which were grouped as insulin pro-
`ducing and non-insulin producing) and the nonhyperfunctioning tumors.
`
`Resuits
`
`The sizes, imaging features, and distribution of the various
`hyperfunctioning and nonhyperfunctioning islet cell
`tumors
`are given in Table 1. Of the hyperfunctioningislet cell tumors,
`insulinomas were the most common and the smallest, with a
`mean diameter of 2.2 cm. Most insulinomas (35 of 43) were
`solid homogeneous masses(Fig. 1). All eight lesions that had
`
`TABLE 1: Imaging Features of Hyperfunctioning and Nonhyperfunctioning Islet Cell Tumors
`
`No. of Tumors with the Following Imaging Features?:
`No. of
`No. of
`size
`SH
`HE
`Cc
`CA
`LI
`vl
`DM
`Tumor
`Patients
`Lesions
`
`Insulinoma
`39
`43
`2
`35
`8
`3
`4
`11
`8
`4
`Gastrinoma
`18
`18
`4
`15
`3
`2
`4
`6
`3
`4
`
`6
`2
`4
`2
`6
`6
`5
`6
`11
`11
`Glucagonoma
`0
`3
`3
`1
`6
`3
`2
`7
`5
`5
`Stomatostatinoma
`0
`0
`2
`1
`0
`0
`4
`4
`4
`4
`Vipoma
`0
`2
`2
`2
`2
`0
`2
`5
`2
`2
`ACTH?producing
`40
`40
`5
`28
`12
`12
`10
`17
`7
`12
`Non-insulin producing°
`
`45
`50
`8
`14
`36
`27
`15
`24
`13
`11
`Nonfunctioning
`124
`133
`5
`77
`56
`42
`30
`52
`28
`27
`Total
`
`
`4Size = mean diameter in centimeters, SH = solid homogeneous appearance, HE = heterogeneous appearance, C = cystic appearance, CA = calcification,
`LI = local invasion, VI = vascular invasion, DM = distant metastases.
`DACTH = adrenocorticotropin hormone.
`©Subtotalfor functioning tumors, excluding insulinomas.
`
`eyes ae Fig. 1.—22-year-old woman who hadInsulino-
`
`ma and whose symptomsincluded confusion,
`agitation, blurred vision, and hypoglycemia.In-
`sulinomasare usually small solid lesions, as in
`this case.
`A, Intraoperative sonogram showssolid iso-
`echoic masswithin tail of pancreas (TAIL PANC);
`mass measured approximately 2 cm in diameter.
`8, Contrast-enhanced CT scan shows homo-
`geneously enhancing solid mass within tail of
`pancreas.
`
`West-Ward Pharm.
`Exhibit 1007
`Page 002
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`AJR:165, November 1995
`
`ISLET CELL TUMORS OF PANCREAS
`
`1177
`
`cystic components seen on gross examination and on imag-
`ing studies were larger than the mean. Calcification,
`local
`invasion, vascular invasion, and distant metastases were less
`common than with nonhyperfunctioning tumors.
`The 18 gastrinomas were larger than the insulinomas
`(mean diameter, 4.2 cm). The majority of these lesions (15 of
`18) also were solid homogeneous masses.Thethree lesions
`that had cystic characteristics measured 1, 6, and 3 cm. Vipo-
`
`mas were similar in size to gastrinomas (4.1 cm) and wereall
`solid homogeneous masses. The other hyperfunctioning islet
`cell tumors, including glucagonomas, somatostatinomas, and
`ACTH-producing tumors, were larger (Figs. 2 and 3).
`The nonhyperfunctioning isiet celi
`tumors had a mean
`diameter of 7.7 cm. Thirty-six of these tumors had heteroge-
`neous areas, and overhalf (n = 27) had cystic degeneration
`(Fig. 4). Only 14 of the 50 nonhyperfunctioning tumors were
`
`contrast-enhanced T1-weighted image (C).
`
`Fig. 2.—69-year-old woman who had glu-
`cagonoma and whose symptoms included rash
`and painful glossitis. Six-centimeter mass noted
`within tail of pancreas had crescentic area of cys-
`tic degeneration (arrow). Note central area of cal-
`cification (arrowhead). Note also evidence of
`vascular invasion into splenic vein, with multiple
`perisplenic varices. Metastasis was noted within
`liver (not shown). These findings were document-
`ed at attempted surgical resection. Calcification
`and vascular invasion are commonfindings with
`such non-insulin-producing tumors as well as
`with nonhyperfunctioningislet cell tumors.
`
`Fig. 3.—42-year-old man who had necrotizing
`migratory erythema caused by glucagonoma. CT
`scan shows 10-cm heterogeneous mass with inter-
`nal focus of cystic degeneration. Hypodense fiver
`metastases also were noted. Cystic degeneration
`and metastatic disease are commonfindings with
`nonhyperfunctioning islet cell tumors as well.
`
`Fig. 4.—45-year-old man who had nonfunc-
`tional islet cell tumor and whose symptomsin-
`cluded 8-month history of vague abdominal pain.
`Large lesions such as this one are predisposed
`to cystic degeneration and aggressive behavior
`(splenic vein invasion was noted on this image
`as well as on other images [not shown)).
`A, Sonogram shows well-circumscribed 10-
`cm mass with large anechoic central area and
`acoustic enhancement compatible with cystic
`degeneration.
`8B, Contrast-enhanced CT scan showscentral
`area offluid attenuation similar to attenuation of
`gallbtadder. Thickline of enhancing viable tumor
`was noted aroundperiphery.
`Cand D, Contrast-enhanced T1-weighted (6851/
`15 [TR/TE]) (C) and T2-weighted (6751/90)(D) axial
`MR images confirm central cystic degeneration.
`Decreased signal intensity on T1-weighted image
`and markedly increased signal intensity on T2-
`weighted image parailei signal intensity of CSF.
`Enhancingviable tumor was noted peripherally on
`
`West-Ward Pharm.
`Exhibit 1007
`Page 003
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`AJR:165, November 1995
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`
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`Fig. 5.—60-year-old man with nonhyperfunc-
`tioning islet cell tumor. Tumor showscystic de-
`generation,calcification, and liver metastasis.
`A, Lobulated 13-cm mass was noted within
`head of pancreas. Note central areas of cystic
`degeneration with attenuation similar to that of
`gallbladder. Small punctate area of calcification
`also wasnoted(arrow).
`B, Unenhanced CT scan showslarge metasta-
`sis within right lobe ofliver (arrows), typical fea-
`ture of nonhyperfunctioningislet cell tumors.
`
`solid homogeneous masses. Local invasion, vascular inva-
`sion, calcification, and distant metastases were more com-
`monthan with insulinomas (Fig. 5).
`Twenty-seven of the 40 tumors with cystic components
`were nonhyperfunctioning islet cell tumors. Heterogeneous
`areas corresponding to necrosis or cystic degeneration were
`noted in 56 tumors with a mean diameter of 8.4 cm. The
`mean diameter of the cystic tumors was 7.9 cm. Thirty-six of
`the tumors with heterogeneous areas were nonhypertunc-
`tioning islet cell tumors. Solid homogeneous masses were
`seen in 76 cases. Only 14 of these lesions were nonhyper-
`functioning islet cell tumors. The mean diameterof the solid
`homogeneous tumors was 2.9 cm.
`Using an analysis of variance and Duncan’s multiple-
`range test, we found the difference in mean diameter
`between the two largest groups, insulinomas and nonhyper-
`functioning tumors, to be statistically significant (o = .0001).
`Using a t¢ test, we found a statistically significant correlation
`between the size of the tumors and whether they were cystic
`(p < .0005), solid homogeneous (p = .0001), or heteroge-
`neous (p = .0001). Similarly, we foundstatistically significant
`differences in size between tumors that were cystic (mean
`diameter, 7.9 cm) or heterogeneous (mean diameter, 8.4
`cm) and solid homogeneous tumors (mean diameter, 2.9
`cm) (p = .0001 for both comparisons).
`A statistically significant correlation between the size of
`the tumors and the presenceof all the characteristics that
`we analyzed also was documented: calcification (mean
`diameter, 8.2 cm) (p < .00005), local invasion (mean diame-
`ter, 6.5 cm) (p = .00006), and vascular invasion (mean diam-
`eter, 7.2 cm) (p = .0019). The larger the tumor, the more
`likely it was to contain all of these features.
`Wealso found statistically significant differences in the
`internal morphology of the tumors, depending on whether
`they were hyperfunctioning or nonhyperfunctioning. Hetero-
`geneity wassignificantly correlated with nonhyperfunctioning
`tumors (p < .0005, x2 test).
`Liver metastases were least common with insulinomas.
`Liver metastases were seen with both ACTH-producing
`tumors, with six of 10 glucagonomas(Fig. 3), and with 11 of
`50 nonhyperfunctioning islet cell tumors (Fig. 5).
`
`Discussion
`
`All islet cell tumors are capable of producing polypeptides.
`Although individual tumors may elaborate more than one
`hormone to various degreesin different parts of the tumor,
`the vast majority of patients have symptoms related to the
`overproduction of a single hormone or have no hormone-
`related symptomsatall [1-5]. However, becauseof this vari-
`ability, islet cell tumors can be divided, on clinical grounds,
`into hyperfunctioning and nonhyperfunctioning tumors.
`Hyperfunctioning tumors may be subdividedinto insulin-pro-
`ducing and non—insulin-producing types.
`Our data demonstrate that size, function, consistency, and
`malignant behavior are integrally related. The most common
`hyperfunctioningislet cell tumors, the insulinomas, were typi-
`cally small homogeneous masses measuring about 2 cm in
`diameter. Cystic changes and necrosis were uncommonfea-
`tures. On the other hand, nonhyperfunctioning istet cell
`tumors were typically larger, heterogeneous tumors with a
`propensity for cystic degeneration and central areas of necro-
`sis; these tumors measured almost 8 cm in diameter. These
`differences were statistically significant, although there was
`some overlap. The other hyperfunctioning islet cell tumors,
`including gastrinomas, glucagonomas, somatostatinomas,
`vipomas, and ACTH-producing tumors, were, as a group,
`larger than the insulinomas and shared a numberof the char-
`acteristics noted for nonhyperfunctioningislet cell tumors.
`In our study, larger tumors, regardless of their hyperfunc-
`tioning or nonhyperfunctioning status, were morelikely to
`be associated with cystic and necrotic areas, calcification,
`local
`invasion, vascular
`invasion, and liver or distant
`metastases. Other associations,
`in fewer patients, have
`been found between nonhyperfunctioning tumors and the
`presenceof calcification [6, 7], increased size and necrosis
`[8], and metastases [9]. Seven of 10 islet cell tumors with
`calcification were shown to have malignant characteristics
`[10]. Venous invasion was shown in 10 of 76 patients with
`islet cell tumors; seven of these 10 patients had hepatic
`metastases [11]. However, not all of these findings have
`been specifically addressed in a large series and correlated
`with the size, consistency, and functional status of
`the
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`AJR:165, November 1995
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`ISLET CELL TUMORS OF PANCREAS
`
`1179
`
`tumor, as we have done in this study. Larger surgical and
`pathologic series have not addressed these associations
`directly [6, 7, 12, 13].
`Direct correlation between the size of the tumor and cys-
`tic or necrotic areas has not yet been formally addressed,
`probably because the research done so far has included
`predominantly surgical series in which the external appear-
`ance was emphasized [12]. Cross-sectional imaging allows
`assessmentof the internal structure as well. Before this
`study, cystic changeswithin islet cell tumors were viewed as
`rare, with only 20 cases previously being reported [14]—
`partly because the surgical community is not familiar with
`these tumors [15] and partly because the tissue examined
`by pathologists and prepared for slides is, appropriately,
`from the solid portion of
`the tumor. Also,
`these earlier
`reports concerned tumors that were predominantly cystic,
`notpartially cystic.
`The cases consideredin this study were collected from a
`large referral population. Thus, our findings are unavoidably
`biased in that regard. However, the proportion of hypertunc-
`tioning islet cell tumors in our series parallels that noted in
`larger epidemiologic studies [5, 16, 17], supporting the
`veracity of the sampling even if
`it was not from a single
`patient population. An additional deficiency is that the imag-
`ing studies and protocols were acquired without the benefit
`of standardized equipment. However, our analysis of the
`gross specimensand surgical reports helped ensure that the
`radiologic interpretation of these cases wascorrect.
`In summary, we have demonstrated an association among
`size, consistency, behavior, and functionofislet cell tumors.
`Smaller tumors tend to be homogeneous masses without
`local invasion or distant metastases andtypically are insuli-
`nomas. Larger tumors more commonly demonstrate cystic
`changes, necrosis, calcification,
`local
`invasion, vascular
`invasion, and distant metastases and are nonhyperfunction-
`ing lesions or are associated with a less clinically evident
`functional syndrome than that seen with insulinomas. Knowl-
`edgeof these features is important to radiologists in identify-
`ing and characterizing masses within the pancreas.
`
`ACKNOWLEDGMENTS
`
`Weare indebted to all the radiologists and pathologists whose
`contributions of outstanding cases to the Armed ForcesInstitute of
`Pathology have madethisarticle possible.
`
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`14. Takeshita K, Furui S, Makita K, et al. Cystic islet cell tumors: radiologic
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`16. Watson RGP, Johnston CF, O'Hare NMT,et al. The frequency of gas-
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`17. Service FJ, McMahon MM, O'Brien PC, Ballard DJ. Functioning insuli-
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`10.
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