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From the Departments of Pathology,*
Oncology,¶
and Surgery,§
The Johns Hopkins University School of Medicine, Baltimore, Maryland;
the Department of Pathology,||
Academic Medical Center,
University of Amsterdam, Amsterdam, The Netherlands; the Department of
Laboratory Medicine and Pathobiology,
University of Toronto, Toronto, Canada; and the Department of
Pathology,
Wayne State University,
Detroit, Michigan
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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.4-8
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Although these preliminary findings favor a distinct pathogenetic course for medullary pancreatic carcinomas, the small number of cases studied so far has required a cautious view. To further elucidate the clinical and genetic features associated with the medullary morphology, we studied a larger series of medullary pancreatic carcinomas. Specifically, our goals were to determine 1) the frequency of wild-type K-ras genes and MSI among medullary carcinomas; 2) whether immunohistochemistry for the DNA-repair gene products Mlh1 and Msh2 could identify the medullary carcinomas with MSI; and 3) whether the medullary carcinomas were associated with any other immunohistochemical, pathological, or clinical variables, including latent Epstein-Barr (EBV) infection or family history of cancer. Answering these three questions would help us to gauge the utility of classifying medullary carcinomas as a special subset of ductal adenocarcinomas of the pancreas.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The surgical pathology files of The Johns Hopkins Hospital and the Academic Medical Center (University of Amsterdam) were screened for pancreatic carcinomas with the medullary histological pattern.4 A histological review of 450 randomly chosen pancreatic cancers revealed 18 (4.0%) possible medullary carcinomas, each originally diagnosed as a poorly differentiated ductal adenocarcinoma. Five of these cases were those originally identified by Goggins et al.4 One of the medullary carcinomas also contained adenosquamous carcinoma comprising approximately half of the neoplasm. All 17 of the remaining medullary carcinomas were pure medullary carcinomas.
The 18 medullary carcinomas were then pooled by a reference pathologist (REW) with 17 other (nonmedullary) pancreatic carcinomas. The 17 nonmedullary carcinomas included 10 poorly differentiated ductal adenocarcinomas, four moderately differentiated ductal adenocarcinomas, two mucinous adenocarcinomas, and one adenosquamous carcinoma. One slide from each case was coded, and the set of slides was reviewed by three other pathologists (GJAO, RHH, and NVA), one of whom (NVA) was from an institution not associated with our original study on medullary carcinomas.4 Each pathologist graded the cases according to criteria originally proposed by Goggins et al4 (gland formation, invasion pattern, syncytial growth pattern, necrosis). Each neoplasm then received an overall grade from 1 (most similar) to 5 (least similar), based on its similarity to the index medullary carcinoma case identified in the original study by Goggins et al.4
A neoplasm was considered a medullary carcinoma only when it met the following two criteria: first, an average grade less than 3; and second, at least two of the three pathologists providing a grade of 2 or lower. The three pathologists were said to disagree when any of the pathologists gave a score that was more than one point away from either of the other two pathologists.
Histological Analysis for Pancreatic Intraepithelial Neoplasias
When available, sections containing nonneoplastic pancreatic tissue surrounding each medullary carcinoma were histologically analyzed by the reference pathologist (REW) for associated pancreatic intraepithelial neoplasias (PanINs), the putative precursors of pancreatic ductal adenocarcinoma.14-16 PanINs were identified and graded according to accepted criteria established at a National Cancer Institute-sponsored Pancreas Cancer Think Tank, held September, 1999, in Park City, Utah. These criteria are available on the Worldwide Web (http://pathology.jhu.edu/pancreas/panin).
In Situ Hybridization for Epstein-Barr Virus
Because they share some features with EBV-containing lymphoepitheliomas of the nasopharynx, all 18 medullary carcinomas were assayed by in situ hybridization for Epstein-Barr virus-encoded RNA-1. In addition, five of the 17 nonmedullary carcinomas were also studied for latent EBV infection. These five nonmedullary carcinomas included two poorly differentiated conventional adenocarcinomas, one moderately differentiated conventional adenocarcinoma, and two mucinous adenocarcinomas.
Formalin-fixed, paraffin-embedded tissue sections were deparaffinized and hydrated in graded ethanol. Sections were washed in water, digested with 10 µg/ml of proteinase K in 50 mmol/L Tris-HCl (pH 7.5) for 30 minutes at 37°C, and washed again in water. Sections were hybridized at 37°C for 16 to 18 hours with 20 µl of fluorescein isothiocyanate-labeled Epstein-Barr virus-encoded RNA riboprobe in hybridization solution (Novocastra, Newcastle on Tyne, UK). A parallel section was hybridized with a negative control probe. The sections were washed in Tris-buffered saline (pH 8.0) with 0.05% Tween 20 (TBS-T; Sigma Chemical Co., St. Louis, MO) and then immersed in 0.2x sodium chloride-sodium citrate/0.1% sodium dodecyl sulfate solution at 52°C for 10 minutes.
Sections were incubated in 10% normal rabbit serum for 30 minutes and then in a 1:200 dilution of anti-fluorescein isothiocyanate-alkaline phosphatase conjugate (In Situ Hybridization Detection Kit, Novocastra) in Tris-buffered saline (pH 8.0) with 0.05% Tween 20 for 30 minutes. After three washes, sections were placed in 1x alkaline-phosphatase buffer (100 mmol/L Tris-HCl, pH 9.5, 100 mmol/L NaCl, 50 mmol/L MgCl2) for 5 minutes. Chromogenic detection was then performed with nitroblue tetrazolium and X-phosphate. Adequate color development occurred within 2 hours of incubation in the chromogen solution. The slides were rinsed in water, counterstained with hematoxylin, and mounted with aqueous mounting medium (GlycerGel; DAKO, Carpinteria, CA). An intense bluish-purple color indicated a positive hybridization signal.
Microdissection and DNA Extraction
The five medullary carcinomas originally identified by Goggins et al4 had already been analyzed genetically. Therefore, 13 genetically unanalyzed medullary carcinomas remained. We also genetically analyzed five of the 17 nonmedullary pancreatic carcinomas with the same technique to ensure a sensitivity adequate to detect single base-pair genetic alterations. These five nonmedullary carcinomas included those also studied for EBV latent infection by in situ hybridization. Therefore, we microdissected and genetically analyzed 18 carcinomas (13 medullary and five nonmedullary) in this study.
Each of the 18 carcinomas to be genetically analyzed were microdissected from unstained 10-µm sections cut from archived paraffin blocks. The microdissected tissue was deparaffinized, digested with proteinase K, purified by phenol-chloroform extraction, and precipitated, as previously described.9,17 The final product was reconstituted in 50 µl LoTE (3 mmol/L Tris, 0.1 mmol/L ethylenediaminetetraacetic acid, pH 7.5) and stored at -20°C. Because of the solid growth pattern of medullary carcinomas and microdissection with avoidance of lymphocytes, relatively pure samples of carcinoma were obtained. Samples containing at least 200 neoplastic cells were used for each polymerase chain reaction (PCR) below. Both the medullary and adenosquamous components of the mixed medullary carcinoma were separately microdissected.
K-ras Gene Analysis
Portions of exons 1 and 2 (encompassing codons 12, 13, and 61) of the K-ras gene (KRAS2) were amplified by PCR, as previously described.9 Direct cycle sequencing (SequiTherm Excel II, Epicentre Technologies, Madison, WI) was performed using internal primers at an annealing temperature of 60°C. Products were separated on a 6% polyacrylamide gel and subjected to autoradiography.
Unusual K-ras genotypes were confirmed by direct sequencing of an independent PCR product and by sequencing of cloned PCR products (TOPO TA, Invitrogen, Carlsbad, CA). The N- and H-ras genes were not studied in this series, as we found previously that mutations in these two genes do not occur in pancreatic carcinomas, including medullary carcinomas.18,19
Microsatellite Instability Analysis
Evidence of MSI was sought in each of the 18 microdissected
samples by: 1) length analysis of BAT 25 and BAT
26 markers; and by 2) direct sequencing of the polythymidine tract
of the TGFBR2 gene.4,20-22
BAT 25
and BAT 26 sequences were amplified by PCR incorporating
[
]-32P-dCTP, and the products were resolved
with 6% denaturing polyacrylamide gels, as previously
described.4
A portion of the TGFBR2 gene was
amplified by PCR, and the products were cycle sequenced and similarly
resolved.4
The three MSI carcinomas from the previous
study of Goggins et al4
were used as positive controls.
For each of these three loci, gain or loss of at least one nucleotide was regarded as a shift. Each carcinoma tested was found to have either shifts in at least two of the three loci (designated MSI), or shifts at no locus (designated microsatellite stable, MSS). Because carcinomas lacking a mononucleotide shift in at least one of these three markers generally do not have shifts in additional dinucleotide markers, additional markers were not used.4,23
Immunohistochemistry for Mlh1 and Msh2
Immunohistochemical labeling for the products of the MLH1 and MSH2 genes was performed on the current series of 13 medullary and five nonmedullary carcinomas, as well as on three MSI medullary carcinomas identified in the previous series collected by Goggins et al.4 Unstained 6-µm sections were deparaffinized and rehydrated with xylene and graded alcohols. The slides were treated with sodium citrate buffer (10 mmol/L, pH 6.0) and then submitted to microwave antigen retrieval. Endogenous peroxidase was blocked by 20% hydrogen peroxide, and nonspecific binding was blocked by 20% Protein Blocker (Signet Laboratories, Dedham, MA) in buffered saline. After cooling for 5 minutes, the slides were labeled with mouse monoclonal antibodies to Mlh1 (1:50 dilution, clone G168–728; PharMingen, San Diego, CA) or to Msh2 (1:100 dilution, clone FE11; Oncogene Research Products, Cambridge, MA) and incubated overnight at room temperature. Each primary antibody was detected by biotinylated secondary antibodies, avidin-biotin complex, and 3,3'-diaminobenzidine. Sections were counterstained with hematoxylin.24
Cancers interpreted to lack Mlh1 or Msh2 expression required a complete absence of labeling in the nuclei of neoplastic cells. Labeling of nonneoplastic epithelium, stromal cells, or lymphocytes served as an internal positive control in each of the sections.
Germline MLH1 Analysis
One patient in this study had synchronous pancreatic and colonic carcinomas. This patient’s pancreatic carcinoma had a medullary phenotype with microglandular features and MSI, and his colonic carcinoma was an adenocarcinoma that also had MSI. In addition, as will be discussed later, neither carcinoma had immunodetectable MLH1 gene product. Therefore, informed consent was obtained for germline MLH1 analysis under a protocol approved by the institutional review board of The Johns Hopkins Hospital. Conformation-sensitive gel electrophoresis was performed under clinical laboratory conditions at the University of Pennsylvania (Philadelphia, PA).25-28 The results of the analysis were discussed with the patient, and he is currently undergoing genetic counseling.
Clinical and Pathological Data Collection
Clinical and pathological data for each of the patients were obtained from various sources, including the medical records of The Johns Hopkins Hospital and the Academic Medical Center, the surgical pathology databases of The Johns Hopkins Hospital and Academic Medical Center, and The Johns Hopkins Oncology Center’s clinical information system. Specifically, family history was obtained from extensive review of these sources. Fourteen (78%) of the 18 patients with medullary carcinomas and 69 (90%) of the 77 patients with nonmedullary carcinomas had familial cancer pedigrees available. Data collected included tumor size, presence of lymph node metastases at presentation, age, gender, race, smoking history, alcohol history, comorbidities, presenting symptoms, and family history of cancer in a first-degree relative. Comorbidities included a history of myocardial infarction, peptic ulcer disease, peripheral vascular disease, hypertension, chronic or acute pancreatitis, and inflammatory bowel disease. Presenting symptoms included weight loss, abdominal pain, jaundice, nausea/vomiting, and fever/chills.
Statistical Methods
Data from the 18 microdissected tumors first described in this study and 77 xenografted tumors, many previously studied by Goggins et al4 and by others in our laboratory,9 were analyzed. Means were compared with a t-test or Wilcoxon rank sum test when the assumption of normality was not valid. Cross-tabulations were performed using Fisher exact tests.
The statistical endpoint of this study was survival status. Event-time distributions for this endpoint were estimated with the method of Kaplan and Meier29 and compared using the log-rank statistic30 or the proportional hazards regression model.31 The simultaneous effect of two or more factors was studied using the multivariate proportional hazards regression model. Covariates that were marginally significant (P < 0.19) in univariate analyses were entered into the multivariate regression model, and nonsignificant effects were removed in a stepwise fashion.
All P values are two-sided. Computations were performed using the Statistical Analysis System32 or EGRET.33,34
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Results |
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The reference pathologist selected 35 cases for histological
study. These included 18 cases classified as medullary by the reference
pathologist and 17 cases classified as nonmedullary. The three other
reviewing pathologists verified the diagnosis of medullary carcinoma in
each of the 18 cases selected by the reference pathologist. The
distribution of average grades for the similarity of the case in
question to the index medullary carcinoma case was as follows: 1.0 (3
carcinomas); 1.2 (2 carcinomas); 1.8 (2 carcinomas); 2.0 (4
carcinomas); 2.1 (1 carcinoma); 2.2 (3 carcinomas); 2.3 (1 carcinoma);
and 2.7 (2 carcinomas) (Table 1)
. The
medullary component from the case also containing adenosquamous
carcinoma received an average grade of 1.8. The distribution of average
scores for the 17 nonmedullary carcinomas was as follows: 5.0 (16
carcinomas) and 4.5 (1 carcinoma).
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Whereas all of the medullary carcinomas had syncytial growth patterns,
expanding tumor borders, and extensive necrosis, some had additional
special features. For example, two medullary carcinomas had foci of
clear cells, one had a focal microglandular growth pattern, and one had
areas of squamoid differentiation (Table 1)
. In addition, one medullary
carcinoma had lymphoepithelioma-like features, with extensive
intraepithelial and stromal infiltration by lymphocytes (Figure 2A)
. In general, pancreatic medullary
carcinomas do not have a large number of intratumoral lymphocytes, as
was seen in this latter neoplasm.4
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When available, slides of pancreatic parenchyma surrounding each of the medullary carcinomas were searched for PanIN. Slides of noncancerous tissue were available from 11 (61%) of the 18 medullary carcinomas (average of 7.2 slides per case; range, 2 to 25 slides). Five (45%) of these 11 cases had PanINs: case 4 had two PanINs-1B, case 5 had one PanIN-1B, case 7 had four PanINs-1A, case 8 had one PanIN-1B, and case 11 had two PanINs-1A and seven PanINs-1B. No higher grade duct lesions (PanINs-2 or -3) were identified.
In Situ Hybridization for Epstein-Barr Virus RNA
All 18 medullary carcinomas and five nonmedullary carcinomas were
probed for latent EBV infection by in situ hybridization
against Epstein-Barr virus-encoded RNA-1. The nuclei of the neoplastic
cells in one (6%) of the 18 medullary carcinomas strongly labeled for
the virus-encoded RNA (Figure 2B)
. The neoplasm demonstrating EBV
infection was the one with lymphoepithelioma-like features. None of the
other 17 medullary carcinomas and none of the five nonmedullary
carcinomas contained EBV RNA.
Prevalence of K-ras Mutations
Each of the 18 microdissected carcinomas produced amplifiable
K-ras PCR products. Of the 13 medullary carcinomas, nine
(69%) had wild-type K-ras genes. This included the
medullary carcinoma with an admixed adenosquamous carcinoma; both
components in this single tumor had wild-type K-ras genes.
In contrast, all five of the microdissected carcinomas without
medullary histology had K-ras mutations
(P = 0.0294). A group of 77 previously
xenografted pancreatic carcinomas, many previously studied by Goggins
et al4
and by others in our laboratory, were also used as
a control. Five (6%) of these 77 had the medullary phenotype, and 72
(94%) were conventional ductal adenocarcinomas. Three (60%) of the
five medullary carcinomas had wild-type K-ras genes, whereas
only four (5.6%) of the 72 conventional ductal adenocarcinomas had
wild-type K-ras genes.35
Thus, medullary
pancreatic carcinomas are more often wild type at the K-ras
gene than are conventional ductal adenocarcinomas
(P = 0.0044). Table 2
summarizes these data.
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Sixty-eight (94%) of the 72 xenografted conventional ductal adenocarcinoma controls harbored K-ras gene mutations. Sixty-six of these were at codon 12, two were at codon 13, and one was at codon 61. One xenografted conventional adenocarcinoma harbored both a GTT (val) mutation at codon 12 and a TGC (cys) mutation at codon 13. This dicodon mutation also had not previously been seen in a human tumor. It was confirmed by repeat direct sequencing of an independent PCR product. Cloning and sequencing of the PCR products established that these two mutations were on the same allele. Two of the five medullary carcinomas in the previous series collected by Goggins et al4 had K-ras gene mutations, and these were GAT (asp) and GCT (ala) changes at codon 12, respectively.
Table 3
summarizes the types of mutations
occurring in medullary and nonmedullary carcinomas of the pancreas.
Figure 3
presents examples of a wild-type
and a mutant K-ras codon 12 in a medullary carcinoma and a
conventional ductal adenocarcinoma, respectively.
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Each of the 18 microdissected pancreatic carcinomas also produced amplifiable BAT 25, BAT 26, and TGFB2 receptor gene products. One (7%) of the 13 microdissected medullary carcinomas had MSI. This carcinoma had shifts with both BAT 25 and BAT 26 markers and had only nine (versus the normal 10) thymidines in the polythymidine tract of its TGFBR2 receptor gene. None of the other 17 microdissected carcinomas had shifts with any of the three markers. Also, three of the five previously xenografted medullary carcinomas originally reported by Goggins et al4 were MSI. If we combine these two series of patients, a total of 4 (22%) of 18 xenografted and microdissected medullary carcinomas had MSI.
This contrasts with a combined total of 77 carcinomas with nonmedullary
histologies, wherein none had MSI. The difference in MSI frequency
between medullary carcinomas and nonmedullary carcinomas was
significant (P = 0.001). Table 2
summarizes
these microsatellite data. Figure 4
illustrates the BAT 25 and BAT 26 PCR products of
several tumors, including the microsatellite unstable tumor described
in this study.
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Immunohistochemistry for MLH1 and MSH2 gene
products was performed on each of the 18 cases from this study and on
the three MSI cases from the previous study of Goggins et
al.4
All four of the MSI cases from these two studies had
absent Mlh1 expression and intact Msh2 expression (Figure 5)
. Expression of both Mlh1 and Msh2 was
intact in all of the MSS cases. Therefore, the sensitivity and
specificity of immunohistochemistry for DNA repair gene enzymes, in the
identification of the genetically proven MSI tumors, were both 100%.
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The microdissected MSI carcinoma with no Mlh1 expression in the
current series originated in a 34-year-old patient with synchronous
carcinomas of the pancreas and colon. Three lines of evidence suggest
that these two carcinomas represented two independent primaries. First,
the pancreatic carcinoma had a medullary pattern with focal
microglandular features, whereas the colonic tumor was, at least
partially, frankly gland-forming. Second, the gross appearance of both
tumors was typical of a primary carcinoma. Third, whereas the
pancreatic primary was associated with multiple lymph node metastases
to peripancreatic nodes, the colonic carcinoma had no lymph node
metastases to surrounding mesenteric nodes. In addition, at the time of
the operation to remove both primaries, no liver metastases were
clinically present. Figure 6
compares the
histology of both carcinomas.
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Because both carcinomas were MSI, informed consent was also obtained for germline analysis of MLH1. Again, a commercial laboratory (University of Pennsylvania, Philadelphia, PA) performed this assay. Conformation-specific gel electrophoresis did not reveal an alteration in the germline copies of this patient’s MLH1 gene.25-28 The patient and his family have undergone genetic counseling at The Johns Hopkins Oncology Center.
Analysis of Medullary Phenotype and Clinicopathological Variables
Multiple clinical, pathological, and genetic variables were
analyzed for associations with the medullary phenotype. These analyses
were performed using the combined total of 18 medullary carcinomas
identified in this study and in the previous study of Goggins et
al.4
The medullary carcinomas were compared to the 77
well-characterized nonmedullary carcinomas (Table 2)
.
The only variables significantly associated with the medullary
phenotype were a family history of any cancer (excluding basal cell and
squamous cell of skin) in a first-degree relative
(P = 0.0004), MSI (P =
0.0010), and a wild-type K-ras gene
(P < 0.0001). Table 4
summarizes these data.
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We also examined the National Familial Pancreas Tumor Registry at The Johns Hopkins Hospital to determine whether any members of families with hereditary pancreas cancer syndromes had medullary cancers. These syndromes included the breast/pancreas cancer syndrome (associated with mutations in BRCA2),38,39 familial atypical mole-malignant melanoma syndrome (associated with mutations in p16),40 and Peutz-Jeghers syndrome (associated with mutations in STK11/LKB1).41 No cases of medullary carcinoma were found among patients with these hereditary syndromes.42
The presence of the medullary phenotype, a mutated K-ras gene, or MSI did not impact survival significantly. Overall 2- and 5-year survival for the 18 patients with medullary carcinoma was 29% and 13%, respectively.
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Discussion |
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The difference in MSI prevalence between the original study by Goggins et al4 and the current study might be explained by the difference in study designs. The original study was a retrospective study in which a separate set of xenografted carcinomas having MSI were identified and subsequently studied histologically. In contrast, the present study represents a prospective analysis of the genetic changes within 13 cases specifically selected for their medullary histological phenotypes.
Second, this present study demonstrates that immunohistochemistry for DNA repair enzymes can identify patients whose medullary pancreatic carcinomas have MSI. Therefore, it may be reasonable to use immunohistochemistry for Mlh1 and Msh2 as a first step to screen medullary pancreatic carcinomas for MSI. Those that have a loss of labeling could then be tested for MSI using microsatellite markers.
Third, medullary carcinomas represent the first instance in which pancreatic tumor histology may be used to identify an inherited susceptibility to cancer. This inherited susceptibility may occur in two ways. For example, we found that the medullary phenotype correlates significantly with family history of any cancer in a first-degree relative. Therefore, where appropriate, the identification of a medullary carcinoma of the pancreas should spur investigation of the cancer incidence among a patient’s relatives. Also, one of the patients included in this study had synchronous MSI pancreatic and colonic cancers, suggesting that he has HNPCC. Indeed, Lynch et al43 reported pancreatic cancer in some HNPCC kindreds. Although the patient in the present study met the clinical criteria for testing for HNPCC, conformation-specific gel electrophoresis studies have yet failed to identify a MLH1 germline mutation. Conformation-specific gel electrophoresis, however, is not 100% sensitive, and this patient may have an unidentified germline MLH1 mutation25-28,44,45 . Sequencing of the entire MLH1 gene and Southern blot analysis would presumably answer this question, but the patient has not requested such studies.
Fourth, medullary carcinomas may represent a subset of ductal adenocarcinomas, rather than a distinct tumor class. This classification is entertained because PanINs are found in nonneoplastic pancreas surrounding almost half of the medullary carcinomas. PanINs are believed to be the precursors to pancreatic ductal adenocarcinoma,14-16 and their presence in tissue surrounding medullary carcinomas suggests that medullary carcinomas may be derived from these precursor lesions. However, no high-grade (and presumably more advanced) PanINs were found near any of the medullary carcinomas. Nor does the mere presence of such precursor lesions necessarily denote that the medullary carcinomas arose from these PanINs.
Fifth, we report here the first case of a pancreatic carcinoma with latent EBV, as demonstrated by in situ hybridization. This medullary carcinoma had lymphoepithelioma-like features, with infiltration of the neoplasm by large numbers of lymphocytes. This finding is not surprising, in that latent EBV infection is common in lymphomas, nasopharyngeal lymphoepitheliomas, and lymphoepithelioma-like neoplasms in other sites, such as the stomach.46-48 Therefore, medullary carcinomas may comprise two distinct subsets: those associated with and those not associated with EBV infection. A larger number of nonmedullary carcinomas will need to be studied to determine whether EBV infection also is associated with a minority of nonmedullary carcinomas as well.
In summary, we conclude that pathologists should distinguish medullary carcinomas from conventional ductal adenocarcinoma for two reasons. First, carcinomas with the medullary phenotype may have a distinct pathogenesis. Only by separating medullary carcinomas from conventional ductal adenocarcinomas will we be able to further define both the genetic changes and the role of EBV in these cancers. Second, medullary carcinomas can be a key clinical clue to the presence of an inherited cancer syndrome, including HNPCC. Further study of this familial association is justified. In the appropriate clinical setting, immunohistochemical studies, microsatellite analysis, germline testing, and genetic counseling may be warranted. In this scenario, immunohistochemical labeling for Mlh1 and Msh2 may help identify MSI in medullary carcinomas and characterize the specific underlying gene defect. More study will also be needed to see if the MSI subset of medullary carcinomas predicts a better survival, as to this date the number of cases is too small to draw conclusions regarding prognosis.
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Acknowledgements |
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Footnotes |
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Supported by the National Institutes of Health Specialized Program in Research Excellence (SPORE) in gastrointestinal cancer (CA62924), the Public Health Service (CA67751–03), the Helen S. Heller and Daniel Kim memorial funds for pancreas cancer research, and The Netherlands Organization for Scientific Research (NWO) (950–10-625).
Accepted for publication January 21, 2000.
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R. H. Hruban, R. E. Wilentz, and S. E. Kern Genetic Progression in the Pancreatic Ducts Am. J. Pathol., June 1, 2000; 156(6): 1821 - 1825. [Abstract] [Full Text] [PDF]
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