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From the First Department of Pathology,*
Niigata
University School of Medicine, Niigata, Japan; and the Department of
Pathology (II),
Juntendo University School of
Medicine, Tokyo, Japan
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A diverse spectrum of intraductal epithelial changes, ie, nonpapillary hyperplasia (non-pap HP), papillary hyperplasia (pap HP), atypical hyperplasia/severe dysplasia, and so forth, has been described around invasive pancreatic carcinomas. Mucous cell hyperplasia has been reported to be the most important precursor in the histogenesis of human pancreatic ductal carcinoma.26-32 However, there have been only a few genetic studies of these pancreatic intraductal preinvasive lesions which correspond to morphology. Using microdissection techniques and extensive allelotyping, Fujii et al23 showed genetic progression and heterogeneity in intraductal papillary-mucinous neoplasms of the pancreas; however, the allelic loss pattern was distinct from solid infiltrating carcinomas. Moskaluk et al6 examined p16 and K-ras mutations in pancreatic intraductal neoplasia accompanied by invasive pancreatic ductal carcinoma, and found frequent p16 alterations to be high-risk precursors of invasive foci.
In the present study, we microdissected multiple foci of ordinary epithelium, non-pap HP, pap HP, severe ductal dysplasia, and invasive foci (invasion, infiltrating components) of solid-type (common type) pancreatic ductal carcinoma. Polymerase chain reaction (PCR)-based microsatellite assays were used to detect loss of heterozygosity (LOH) on chromosome arms 3p, 4q, 5q, 6q, 8p, 9p, 10q, 11q, 13q, 16q, 17p, and 18q. Using this approach, we found evidence of genetic progression and divergence in the intraductal clonal development of solid-type pancreatic ductal carcinoma into the invasive phenotype.
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Materials and Methods |
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Patient demographics are summarized in Table 1
. Patients included six men and four
women. The mean age at the time of diagnosis was 66 (range, 51 to 79)
years old. The TNM staging of these pancreatic carcinomas ranged
from II T2N0 M0/G1 to III T3N1 M0/G1 (Table 1)
.33
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Ten cases of paraffin-embedded tissues diagnosed as severe ductal dysplasia (in situ carcinoma or atypical ductal lesion) adjacent to invasive pancreatic ductal carcinoma were obtained from 166 cases of surgically resected pancreatic ductal carcinoma files between 1976 and December 1997 in the First Department of Pathology at Niigata University School of Medicine. In all pancreatic carcinomas, a formalin-fixed specimen of the whole pancreas was cut into 4- to 5-mm stepwise tissue blocks along the main pancreatic duct and embedded in paraffin.
All pathology was reviewed for consistency of diagnosis using published criteria proposed by the Armed Forces Institute of Pathology (AFIP) for ordinary epithelium, non-pap HP, pap HP, severe ductal dysplasia (carcinoma in situ) which shows severe cellular atypia of duct cells with or without papillary proliferation, and invasive foci.31,32 Intraductal lesions were defined as lesions whose walls had fine circular elastic fibers on Victoria-Blue staining, especially in the main pancreatic duct or in the first and second branches of pancreatic ducts which have accessory mucous glands.
For each case, appropriate tissue blocks were selected, and 3-µm sections were cut and stained with hematoxylin and eosin (H&E) and with antibodies against p53 (PAb 1801 mouse monoclonal antibody; Oncogene Science, Inc., Manhasset, NY) and Ki 67 (antibody MIB-1; Immnotech, Marseille, France). Multiple serial sections 10-µm thick were cut, deparaffinized, stained with H&E, visualized with an inverted microscope, and microdissected using a 26-gauge needle. Two to 15 foci of severe ductal dysplasia, one to six foci of pap HP or non-pap HP, one to three foci of ordinary epithelium, and one to eight invasive carcinoma foci were individually microdissected for each case. The cellular composition of all microdissected foci were regarded as cytologically homogeneous. Most microdissected intraductal lesions were cytologically homogeneous and the entire ductal epithelium was microdissected. However, when a single dysplastic ductal section contained both severely dysplastic and focally nonatypical hyperplastic epithelial cells, only dysplastic cells were microdissected. Normal control tissue (acinar cells) was obtained from nontumorous lobules. Tissue was digested overnight in buffer containing 0.5% Nonidet P-40 and 200 µg/ml of proteinase K at 50°C. A total of 126 foci (8 to 17 foci in each case) including nine ordinary epithelium, 12 non-pap HP, 12 pap HP, 66 severe ductal dysplasia (carcinoma in situ), and 27 invasive foci from 10 cases were microdissected, and allelic status was analyzed for 12 chromosomal arms using 24 microsatellite markers.
Microsatellite Markers
PCR amplification of microsatellite markers was performed using primers for 3p (D3S1234, D3S1293, and D3S1286), 4q (D4S424 and D4S473), 5q (D5S421 and 5S1956), 6q21–25 (D6S264, D6S255, D6S311, and D6S473), 8p (D8S255, D8S261, and D8S264), 9p21 (D9S1748 and D9S1749), 10q (D10S219, D10S547, and D10S574), 11q23.3 (D11S29), 13q12–22 (D13S166, D13S168, and D13S171), 16q12–24 (D16S265 and D16S541), 17p12–14 (D17S122, D17S786, CHRNB1, TP53, and D17S1866), and 18q (D18S46, D18S474, D18S487, and D18S55). All primers were obtained from Research Genetics (Huntsville, AL). Encompassed in these chromosomal regions are several candidate suppressor genes for pancreatic ductal carcinoma, including BRCA2 (13q), Rb1 (13q), p53 (17p),9-13 MKK4 (17p),34,35 E-cadherin (16q), DCC (18q), DPC4 (18q),13,18-20 APC (5q),36,37 and p16/MTS1 (9p).13-17,38
LOH Analysis
PCR reactions contained 1 µl of DNA lysate, 0.4 µCi
[
-32p]ATP-radiolabeled microsatellite primer, 0.2 mmol/L dNTP, 10
mmol/L Tris-HCl, pH 8.3, 1.5 mmol/L MgCl2, 50 mmol/L KCl,
and 0.4 U Taq polymerase in a total reaction volume of 10 µl. The
hot-start method of PCR was used to eliminate nonspecific
amplification. The samples underwent 35 cycles of PCR amplification
(94°C for 30 seconds, 58°C for 40 seconds, and 72°C for 60
seconds) followed by a 2-minute extension at 72°C. PCR products were
separated on a 5% denaturing polyacrylamide-urea-formamide gel and
visualized using a phosphoimager (Bas 2500, Bio Imaging System; Fuji
Film, Tokyo, Japan). LOH was determined from a >75% reduction in the
intensity in one of the two alleles compared with the normal control.
Elimination of PCR Artifacts
A number of previous studies suggested frequent PCR artifacts from paraffin-embedded materials, especially when the number of cells analyzed are small. To exclude all artifactually created allelic imbalances, we used at least 100 cells per PCR reaction. On average, 100 to 200 cells were included in each 10 µl of PCR reaction. Normal controls also contained approximately 100 to 300 nontumor cells per PCR reaction. Because the degree of DNA degradation affects the amplification efficiency and the chance of artifacts, cases and foci which show suboptimal PCR amplifications as well as nonreproducible allelic patterns were excluded. Thus, of the initial 33 cases collected, only 10 cases were selected for the present analysis. Only microdissected foci with reproducible amplifications were included in the present analysis. Because the size of PCR products larger than 200 bp are prone to nonreproducible amplification artifacts, most PCR primers in the present study were chosen to amplify <200 bp.39-42 All PCR reactions which showed homogeneous and heterogeneous LOH were repeated at least three times in duplicate reactions to confirm the findings and to exclude spurious PCR reactions. If necessary, microdissection was repeated.23,43,44 Heterogeneous patterns of allelic losses were also confirmed by other microsatellite markers located on the same chromosomal arms showing the same allelic loss patterns.
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Results |
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The frequency of LOH for each case is shown in Table 2
. When allelic loss of at least one foci
was scored as LOH for each case, the most frequent allelic losses
(>60%) were detected on 9p (non-pap HP 11%, pap HP 17%, severe
ductal dysplasia 90%, invasion 100%), followed by 17p (HP 0%, severe
ductal dysplasia 80%, invasion 80%), 18q (HP 0%, severe ductal
dysplasia 88%, invasion 88%), and 6q (HP 0%, severe ductal dysplasia
63%, invasion 50%). Therefore, 9p- and
17p- followed by 18q- and
6q- were the important allelic losses in
pancreatic ductal carcinoma, not only in invasive foci but also in
severe ductal dysplasia.
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Heterogeneity with respect to allelic loss among different
neoplastic foci of severe ductal dysplasia was found in
80% (8 out of 10: G2, G4, G5, G8, G21, G24, G30,
and G33) of the cases examined. Heterogeneity was also observed among
invasive areas in 57.1% (four of seven cases in which multiple
invasive areas were dissected: G2, G24, G25, and G31) (Table 3)
. For
severe ductal dysplasia, the heterogeneity index was calculated as the
number of cases with heterogeneous patterns of allelic loss of the
chromosomal arms in severe ductal dysplasia divided by the total number
of cases with at least one dysplastic foci showing LOH (Table 2)
. A low
heterogeneity index suggests that LOH of a particular chromosomal arm
occurred relatively early in the dysplastic foci. LOH of chromosomal
arms with a high heterogeneity index is considered a late event in the
intraductal neoplastic process. Both 9p (11%) and 17p (13%) showed
low heterogeneity indexes, thus, these chromosomal losses were
considered to have occurred early. LOH of 18q (heterogeneity index,
50%) and 6q (heterogeneity index, 40%) were still assumed to have
occurred early in the dysplasia, but may have followed 9p and 17p LOH
as shown for G2 and G33 below.
Two examples of heterogeneous patterns of LOH from HP to invasive
carcinoma through severe ductal dysplasia are illustrated for G2
(Figure 1
for distribution of the foci
microdissected and representative histology, Figure 2
for representative gels and deduced
sequence of genetic alterations) and G33 (Figure 3
for distribution of the foci
microdissected and representative histology, and Figure 4
for representative gels and deduced
sequence of genetic alterations). When both alleles of the same
chromosome were independently lost from different foci, LOH
and
LOHß were used for the designation. To clarify the heterogeneous
patterns of LOH, gels of the two different markers on the same
chromosomal arms are shown for 6q, 18q, and 3p.
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of 6q and 18q was seen not only in
severe ductal dysplasia (T1, T2, T3, T7, and T9) but also in invasion
(T4, T5, and T11). In contrast, the LOH ß of 6q, 18q was seen only in
severe ductal dysplasia (T8, T10, and T15). In the three invasive foci
microdissected (T4, T5, and T11), further divergent and progressive
genetic changes were detected at 3p and 13q. Summarizing case G2, the
clonal neoplastic process started with early and homogeneous LOH at 9p
and 17p, with subsequent genetic divergence resulting in different
allelic loss patterns of 6q, 18q, 10q, 3p, and 13q, some of which were
seen in some dysplastic and invasive foci (Figure 2
, right).
For case G33, LOH of 9p and 17p was detected in all microdissected
dysplastic and invasive foci, indicating that these clonal chromosomal
alterations occurred early in the intraductal stage. The neoplastic
clone subsequently diverged into two genetic pathways; one pathway
developed into invasive foci with 18q- and the
other subclone with 6q- and
18q-ß was exclusively seen in intraductal foci.
Spatial Distribution of Genetic Heterogeneity
As shown in Figure 1, B and C
, for G2 and in Figure 3B
for G33,
foci with identical genetic changes were clustered in a certain area in
all cases that showed heterogeneous LOH. Genetically heterogeneous
but closely related foci were clustered and located nearby. Thus, all
genetic progression and heterogeneity occurred in spatially continuous
manners within the ducts. The clustering of foci with heterogeneous
genetic changes also excludes the possibility of PCR artifacts, which
most likely produce a random distribution of heterogeneity.
Concurrent Allelic Loss of Chromosomal Regions
Concurrent alterations of multiple loci (more than two) of LOH were more common in severe ductal dysplasia (94% of the foci) and invasive foci (96% of the foci) than in HP (3%). Concurrent alterations of these three loci of LOH (9p, 17p, and 18q) in severe ductal dysplasia and invasive foci were evaluated. Coexistence of 9p-, 17p-, and 18q- occurred in 63% of invasive foci and 42% of severe ductal dysplasia. In the remaining foci, coexistence of 9p- and 17p- was observed in 22% of invasion and 38% of severe ductal dysplasia. Coexistence of 9p- and 18q- was observed in 7% of invasion and 12% of severe ductal dysplasia. Coexistence of 17p- and 18q- without 9p- was never observed in either invasion or severe ductal dysplasia.
p53 Immunohistochemistry
Eight of ten cases were strongly stained for p53 in both severe
ductal dysplasia and invasive foci (Table 3
; G2, G4, G5, G21, G25, G30,
G31, and G33). In seven cases (G2, G4, G5, G25, G30, G31, and G33),
both p53 positivity and 17p LOH were detected throughout the dysplastic
intraductal and invasive foci, indicating early inactivation of p53.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the present study, by extensive sampling of intraductal lesions with microdissection and LOH analysis of multiple chromosomal loci, we successfully demonstrated the dynamic and successive accumulation of genetic alterations in early pancreatic intraductal neoplastic foci for the first time.
All foci of severe ductal dysplasia and invasive foci showed LOH at more than one chromosomal locus. For each case, LOH on 9p, 17p, and 18q was frequently observed in invasive areas (9p-, 100%; 17p-, 80%; and 18q-, 88%), similar to previous reports.9,21,22 These high frequencies of LOH on 9p, 17p, and 18q were also detected in individually microdissected severe ductal dysplasia foci (9p- in 95%, 17p- in 83%, and 18q- in 74% of total foci dissected) in the present study. These allelic losses shared by most of the dysplastic foci and invasive foci strongly suggest that the clonal neoplastic process begins early in intraductal dysplastic epithelium.
Heterogeneity of the LOH pattern among dissected severe ductal
dysplasia and invasive foci, as shown in Figures 1, 2, 3, and 4
was
seen in 57% of invasion and in 80% of severe ductal dysplasia. (Table 3)
. In all cases, however, some of the allelic losses identified in the
in situ cancers were generally conserved in the synchronous
infiltrating tumors, supporting the concept that infiltrating tumors
are clonally derived from noninvasive intraductal lesions.
Heterogeneity was either genetic progression, genetic diversion, or a
combination of both. In the genetic progression, there was a linear and
gradual accumulation of LOH from hyperplastic foci to severe ductal
dysplasia to invasive foci. In clonal diversion, the clone with early
genetic changes will diverge, and multiple subclones will expand within
the duct. Only some of these divergent subclones may develop invasive
tumors as shown in G2 and G33. Many pancreas cancers probably evolve by
a combination of these two heterogeneous pathways.
Spatial distributions of genetic heterogeneity were not random but were
strongly indicative of the pathways for clonal neoplastic progression.
Genetically identical foci were all clustered in a certain area and
closely related foci were clustered nearby as shown in Figure 1, B and C, and 3B
. Thus, genetic progression and diversion was assumed to occur
when the clonal neoplastic process continuously spreads within the
duct. At some point, in some foci, the clone assumes invasive
character.
Chromosomal losses common to all tumor foci most likely preceded the chromosomal losses observed only in the tumor foci of more advanced stages. The 9p loss, especially, was detected very early (in HP foci in two cases), and in many cases tended to be clonally homogeneous in multiple dissected foci. Thus, 9p loss and possibly inactivation of p16 occur very early in the intraductal lesions and most likely in the transition from hyperplastic to early severe ductal dysplasia stage. 17p LOH is also relatively homogeneous throughout the intraductal foci and thus occurs early. Successive loss of 18q and 6q follows, still in the intraductal stage. Loss of other chromosomal loci (3p, 4q, 5q, 8p, 10q, and 13q) was less frequent and much more limited in the foci dissected. Thus, these additional losses occur later in the severe ductal dysplasia stage when the neoplastic subclones diverge and expand.
In previous studies of invasive pancreatic ductal adenocarcinoma, using frozen tissues, cell lines, or xenografts, nonrandom LOH on many chromosomes has been reported.21-25 Seymour et al21 described allelic loss of chromosome 18q (86%) and 17p (80%) by analyzing fresh-frozen tissues from seven cases of surgically-resected exocrine adenocarcinomas of the pancreas. Hahn et al22 used xenografts taken from 18 human pancreatic ductal carcinomas and described frequent allelic loss (>60%) for 1p (69%), 9p (89%), 17p (100%), and 18q (89%), in addition, moderately frequent allelic loss (40 to 60%) was seen at 3p (44%), 6p (50%), 6q (53%), 8p (56%), 10q (50%), 12q (56%), 13q (50%), 18p (44%), 21q (56%), and 22q (59%). Mahlamäki et al24 also described a high frequency of LOH for 18q (100%) and 9p (91%) by comparative genomic hybridization.
The specific genetic alterations in adenocarcinomas of the pancreas include activation of the K-ras oncogene in 80 to 100% of cancers13,47-49 and inactivation of p16 (on chromosome 9p)13-17,38 , p53 (chromosome 17p), 9-13 and DPC4 (chromosome 18q).13,18-20 Rozenblum et al13 described the frequencies of tumor suppressor gene inactivation for p16, p53, and DPC4 as 82% (33 of 40), 76% (31 of 41), and 53% (20 of 38) of tumors, respectively, by direct sequencing from xenograft materials. All were accompanied by LOH. Most of these studies, however, have focused on invasive lesions and limited their sampling of in situ foci.
Pancreatic intraductal lesions found around invasive carcinoma have been reported to be precursors to invasive pancreas cancers in histopathological studies.26-31 These lesions have been labeled as nonpapillary hyperplasia (mucous cell hypertrophy), papillary-hyperplasia and severe ductal dysplasia (atypical hyperplasia, carcinoma in situ).30,31,33 Of these, mucous cell hyperplasia has been reported to be the most important early precursor lesion. Severe cellular atypia of ductal epithelium, with or without papillary projection, has been defined as "severe ductal dysplasia" (atypical hyperplasia). Recently, cases with severe ductal dysplasia have been reported to have developed invasive cancer 17 months and 10 years later.50
Few molecular genetic studies of such intraductal pancreatic lesions have been reported. K-ras mutation has been shown to be the most important precursor of pancreatic ductal carcinoma.3-6 Recently, however, K-ras mutation has been observed in mucous cell hyperplasia in chronic pancreatitis and other nonneoplastic lesions.7,8 Moskaluk et al6 described an alteration of the p16 gene in a subset of pancreatic intraductal neoplasia that contains a mutation of K-ras, and they found K-ras and p16 mutations to be important high-risk precursors of invasive disease. Hruban et al32 suggested the possibility that duct lesions are the precursors to infiltrating carcinoma of the pancreas based on both morphological and molecular analyses. The present findings further support the previous studies and confirmed that the clonal neoplastic process starts early in the intraductal stage with early involvement of 9p loss (consistent with alteration of p16), 17p loss and progressive accumulation of other genetic changes during the preinvasive stage.
The p16 alteration is observed in 85% of xenografts or cell lines from pancreatic carcinoma.13,16,38 Schutte et al38 described three patterns in xenografts or cell lines of pancreatic carcinoma: homozygous deletions in 48% (24 out of 50), intragenetic mutations in 36% (18 out of 50), and wild type in 16% (8 out of 50) where methylation of the CpG island occurred in 39% (7 out of 18). Loss of 9p (primers INFA and D9S 171, which were located near the p16 locus) was observed in 98% of all cases, including homozygous deletion and wild type. The present finding of 9p loss is also consistent with these previous studies and further supports the early involvement of p16 in the intraductal stage of the pancreatic neoplasms.
Concurrent alterations of three tumor suppressor genes in tumors were described by Rozenblum et al.13 p53, p16, and DPC4 inactivation were observed in 39.5% (15 out of 38 cases of pancreatic ductal carcinoma), p53 and p16 inactivation in 26.3% (10 out of 38 cases), and p16 and DPC4 inactivation in 13.2% (5 out of 38 cases). However, p53 and DPC4 inactivation without p16 alteration was never observed. In the present study, not only foci of invasion but also foci of severe ductal dysplasia frequently showed coexistent loss of 9p, 17p, and 18q. LOH of 9p, 17p, and 18q, 9p and 17p, and 9p and 18q were frequently detected in both invasive and severe ductal dysplasia foci, whereas 17p and 18q without 9p loss was never observed. Thus, a combination of these three genetic alterations is characteristic of pancreatic ductal carcinoma and tends to be acquired very early in the intraductal stage; 9p loss seems to be an obligatory step for later 17p and 18q loss.
In conclusion, pancreatic ductal carcinomas develop from hyperplasia through severe ductal dysplasia to invasive foci by a progressive and often divergent accumulation of genetic changes, which reflect the spectrum of intraductal morphological alterations around invasive foci. LOH of 17p and 9p is observed at a high frequency in both invasive and severe ductal dysplasic foci, and 9p loss may be the earliest event in the transition from hyperplasia to early dysplasia. Other chromosomal alterations including 18q and 6q follow later in the intraductal dysplastic and invasive stage and confer subclones with a further growth advantage.
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Footnotes |
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Supported in part by a research grant from the Ministry of Education, Science and Culture of Japan.
Accepted for publication March 7, 2000.
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