[Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 54.211.207.116. Please contact the publisher to request reinstatement.
[Skip to Content Landing]
Download PDF
Figure 1.
Sequence chromatogram demonstrating T-to-A mutation at position 377 in exon 2 of the cyclin-dependent kinase inhibitor 2A, which leads to the V126D substitution (substitution of aspartate for valine at amino acid 126).

Sequence chromatogram demonstrating T-to-A mutation at position 377 in exon 2 of the cyclin-dependent kinase inhibitor 2A, which leads to the V126D substitution (substitution of aspartate for valine at amino acid 126).

Figure 2.
Pedigree of a kindred with familial melanoma. The observed-expected ratio for pancreatic carcinoma based on a familial standardized incidence ratio analysis from the founder on the right (double arrow) is 12.658 (P = .002). The observed-expected ratio for pancreatic carcinoma from the founder on the left (triple arrow) is 8.93 (P = .001). The observed-expected ratios of melanoma are 20.89 for the founder on the right (double arrow) and 16.45 for the founder on the left (triple arrow). Our proband is marked with a single arrow. Slight discrepancies in the age at onset (AO) of disease for our proband exist between the pedigree and the case report due to changes in the subject's date of birth to maintain anonymity. Squares indicate male members; circles, female members; diamonds, a group of unaffected members, with the number of members in each group indicated below each symbol; and slashes, dead.

Pedigree of a kindred with familial melanoma. The observed-expected ratio for pancreatic carcinoma based on a familial standardized incidence ratio analysis31 from the founder on the right (double arrow) is 12.658 (P = .002). The observed-expected ratio for pancreatic carcinoma from the founder on the left (triple arrow) is 8.93 (P = .001). The observed-expected ratios of melanoma are 20.89 for the founder on the right (double arrow) and 16.45 for the founder on the left (triple arrow). Our proband is marked with a single arrow. Slight discrepancies in the age at onset (AO) of disease for our proband exist between the pedigree and the case report due to changes in the subject's date of birth to maintain anonymity. Squares indicate male members; circles, female members; diamonds, a group of unaffected members, with the number of members in each group indicated below each symbol; and slashes, dead.

Figure 3.
Histological and immunohistochemical differences between the patient's melanoma and pancreatic carcinoma. A, Metastatic melanoma of the lung (hematoxylin-eosin, original magnification ×200). Sections of the lung mass demonstrate a poorly differentiated neoplasm composed of pleomorphic epithelioid cells arranged in variably sized nests. B, Pancreatic adenocarcinoma (hematoxylin-eosin, original magnification ×200). Sections of the pancreatic mass demonstrate a cytologically malignant neoplasm forming glands with focal mucin production. C, Metastatic melanoma of the lung (S100, original magnification ×200). Neoplastic cells are immunoreactive for S100 but not for Melan-A (DAKO Corporation, Carpinteria, Calif; diluted 1:20) (E, original magnification ×200), HMB-45 (DAKO Corporation; diluted 1:50) (not shown), or cytokeratin AE1/AE3 (G, original magnification ×200). D, Pancreatic adenocarcinoma (S100, original magnification ×100). Neoplastic cells are not immunoreactive with S100 but are strongly positive for cytokeratin AE1/AE3 (F, original magnification ×200). H, Aspirate of peritoneal fluid reveals clusters of malignant cells forming glandular lumina (Wright stain, original magnification ×200). Findings of mucicarmine stain are positive within tumor aggregates (inset [right portion of H], original magnification ×200).

Histological and immunohistochemical differences between the patient's melanoma and pancreatic carcinoma. A, Metastatic melanoma of the lung (hematoxylin-eosin, original magnification ×200). Sections of the lung mass demonstrate a poorly differentiated neoplasm composed of pleomorphic epithelioid cells arranged in variably sized nests. B, Pancreatic adenocarcinoma (hematoxylin-eosin, original magnification ×200). Sections of the pancreatic mass demonstrate a cytologically malignant neoplasm forming glands with focal mucin production. C, Metastatic melanoma of the lung (S100, original magnification ×200). Neoplastic cells are immunoreactive for S100 but not for Melan-A (DAKO Corporation, Carpinteria, Calif; diluted 1:20) (E, original magnification ×200), HMB-45 (DAKO Corporation; diluted 1:50) (not shown), or cytokeratin AE1/AE3 (G, original magnification ×200). D, Pancreatic adenocarcinoma (S100, original magnification ×100). Neoplastic cells are not immunoreactive with S100 but are strongly positive for cytokeratin AE1/AE3 (F, original magnification ×200). H, Aspirate of peritoneal fluid reveals clusters of malignant cells forming glandular lumina (Wright stain, original magnification ×200). Findings of mucicarmine stain are positive within tumor aggregates (inset [right portion of H], original magnification ×200).

Figure 4.
Algorithm for pancreatic carcinoma surveillance in patients with familial melanoma. Surveillance should begin 10 years before the earliest diagnosis of pancreatic carcinoma in the family, or at 50 years of age, which ever comes first. CDKN2A indicates cyclin-dependent kinase inhibitor 2A; EUS, endoscopic ultrasonography; CA 19-9, cancer antigen 19-9; ERCP, endoscopic retrograde cholangiopancreatography; and CT, computed tomography.

Algorithm for pancreatic carcinoma surveillance in patients with familial melanoma. Surveillance should begin 10 years before the earliest diagnosis of pancreatic carcinoma in the family, or at 50 years of age, which ever comes first. CDKN2A indicates cyclin-dependent kinase inhibitor 2A; EUS, endoscopic ultrasonography; CA 19-9, cancer antigen 19-9; ERCP, endoscopic retrograde cholangiopancreatography; and CT, computed tomography.

1.
Goldstein  AMTucker  MA Genetic epidemiology of cutaneous melanoma: a global perspective. Arch Dermatol. 2001;1371493- 1496
PubMedArticle
2.
Piepkorn  MW Genetic basis of susceptibility to melanoma. J Am Acad Dermatol. 1994;311022- 1039
PubMedArticle
3.
Della Ragione  FRusso  GOliva  A  et al.  5′-Deoxy-5′ methylthioadenosine phosphorylase and p16INK4 deficiency in multiple tumor cell lines. Oncogene. 1995;10827- 833
PubMed
4.
Goldstein  AMDracopoli  NCEngelstein  MFrase  MCClark  WHTucker  MA Linkage of cutaneous malignant melanoma/dysplastic nevi to chromosome 9p, and evidence for genetic heterogeneity. Am J Hum Genet. 1994;54489- 496
PubMed
5.
Gruis  NASandkuijl  LAvan der Velden  PABergman  WFrants  RR CDKN2 explains part of the clinical phenotype in Dutch familial atypical multiple-mole melanoma (FAMMM) syndrome families. Melanoma Res. 1995;5169- 177
PubMedArticle
6.
Harland  MMeloni  RGruis  N  et al.  Germline mutations of the CDKN2A gene in UK melanoma families. Hum Mol Genet. 1997;62061- 2067
PubMedArticle
7.
Holland  EABeaton  SCBecker  TM  et al.  Analysis of the p16 gene, CDKN2, in 17 Australian melanoma kindreds. Oncogene. 1995;112289- 2294
PubMed
8.
Hussussian  CJStruewing  JPGoldstein  AM  et al.  Germline p16 mutations in familial melanoma. Nat Genet. 1994;815- 21
PubMedArticle
9.
Ranade  KHussussian  CJSikorski  RS  et al.  Mutations associated with familial melanoma impair p16INK4 function. Nat Genet. 1995;10114- 116
PubMedArticle
10.
Walker  GJHussussian  CJFlores  JF  et al.  Mutations of the CDKN2/p16INK4 gene in Australian melanoma kindreds. Hum Mol Genet. 1995;41845- 1852
PubMedArticle
11.
Lal  GLiu  LHogg  DLassam  NJRedston  MSGallinger  S Patients with both pancreatic adenocarcinoma and melanoma may harbor germline CDKN2A mutations. Genes Chromosomes Cancer. 2000;27358- 361
PubMedArticle
12.
Piepkorn  M Melanoma genetics: an update with focus on the CDKN2A(p16)/ARF tumor suppressors. J Am Acad Dermatol. 2000;42705- 722
PubMedArticle
13.
Ruas  MPeters  G The p16INK4a/CDKN2A tumor suppressor and its relatives. Biochim Biophys Acta. 1998;1378F115- F177
PubMed
14.
Serrano  MHannon  GJBeach  D A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature. 1993;366704- 707
PubMedArticle
15.
Clark  WHReimer  RRGreene  MAinsworth  AMMastrangelo  MJ Origin of familial malignant melanomas from heritable melanocytic lesions: "the B-K mole syndrome." Arch Dermatol. 1978;114732- 738
PubMedArticle
16.
Newton-Bishop  JABataille  VPinney  EBishop  DT Family studies in melanoma: identification of the atypical mole syndrome (AMS) phenotype. Melanoma Res. 1994;4199- 206
PubMedArticle
17.
Vasen  HFAGruis  NAFrantis  RRvan der Velden  PAHille  ETMBerman  W Risk of developing pancreatic cancer in families with familial atypical multiple mole melanoma associated with a specific 19 deletion of p16 (p16-Leiden). Int J Cancer. 2000;87809- 811
PubMedArticle
18.
Bergman  WWatson  Pde Jong  JLynch  HTFusaro  RM Systemic cancer and the FAMMM syndrome. Br J Cancer. 1990;61932- 936
PubMedArticle
19.
Bergman  WGruis  N Familial melanoma and pancreatic cancer [letter]. N Engl J Med. 1996;334471- 472
PubMed
20.
Borg  ASandberg  TNilsson  K  et al.  High frequency of multiple melanomas and breast and pancreas carcinomas in CDKN2A mutation–positive melanoma families. J Natl Cancer Inst. 2000;921260- 1266
PubMedArticle
21.
Ghiorzo  PCiotti  PMartelli  M  et al.  Characterization of ligurian melanoma families and risk of occurrence of other neoplasia. Int J Cancer. 1999;83441- 448
PubMedArticle
22.
Goldstein  AMFraser  MCStruewing  JP  et al.  Increased risk of pancreatic cancer in melanoma-prone kindreds with p16INK4 mutations. N Engl J Med. 1995;333970- 974
PubMedArticle
23.
Hille  ETMvan Duijn  EGruis  NARosendaal  FRBergman  WVandenbroucke  JP Excess cancer mortality in six Dutch pedigrees with the familial atypical multiple mole-melanoma syndrome from 1830 to 1994. J Invest Dermatol. 1998;110788- 792
PubMedArticle
24.
Lal  GLiu  GSchmocker  G  et al.  Inherited predisposition to pancreatic adenocarcinoma. Cancer Res. 2000;60409- 416
PubMed
25.
Schutte  MHruban  RHGeradts  J  et al.  Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas. Cancer Res. 1997;573126- 3130
PubMed
26.
Whelan  AJBartsch  DGoodfellow  PJ Brief report: a familial syndrome of pancreatic cancer and melanoma with a mutation in the CDKN2 tumor-suppressor gene. N Engl J Med. 1995;333975- 977
PubMedArticle
27.
Lynch  HTBrand  RBHogg  D  et al.  Phenotypic variation in eight extended CKDN2A germline mutation familial atypical mole melanoma-pancreatic carcinoma–prone families. Cancer. 2002;9484- 96
PubMedArticle
28.
Not Available, American Gastroenterological Association medical position statement. Gastroenterology. 1999;1171463- 1484
PubMedArticle
29.
Jemal  AThomas  AMurray  TThun  M Cancer statistics 2002. CA Cancer J Clin. 2002;5223- 47
PubMedArticle
30.
Hruban  RHCanto  MIYeo  CJ Prevention of pancreatic cancer and strategies for management of familial pancreatic cancer. Dig Dis. 2001;1976- 84
PubMedArticle
31.
Kerber  RA Method for calculating risk associated with family history of a disease. Genet Epidemiol. 1995;12291- 301
PubMedArticle
32.
Chu  PWu  EWeiss  L Cytokeratin 7 and cytokeratin 20 expression in epithelial neoplasms: a survey of 435 cases. Mod Pathol. 2000;13962- 972
PubMedArticle
33.
Ichihara  TNomoto  STakeda  S  et al.  Clinical usefulness of the immunostaining of the tumor markers in pancreatic cancer. Hepatogastroenterology. 2001;48939- 943
PubMed
34.
Tot  T Adenocarcinomas metastatic to the liver. Cancer. 1999;85171- 177
PubMedArticle
35.
Tot  T The value of cytokeratins 20 and 7 in discriminating metastatic adenocarcinomas from pleural mesotheliomas. Cancer. 2001;922727- 2732
PubMedArticle
36.
Florell  SRCoffin  CMHolden  JA  et al.  Preservation of RNA for functional genomic studies: a multidisciplinary tumor bank protocol. Mod Pathol. 2001;14116- 128
PubMedArticle
37.
Florell  SRZone  JJGerwels  JW Basal cell carcinomas are populated by melanocytes and Langerhans cells. Am J Dermatopathol. 2001;2324- 28
PubMedArticle
38.
Bishop  DTDemenais  FGoldstein  A  et al.  Geographical variation in the penetrance of CDKN2A mutations for melanoma. J Natl Cancer Inst. 2002;94894- 903
PubMedArticle
39.
Newton-Bishop  JAWachsmuth  RCHarland  M  et al.  Genotype/phenotype and penetrance studies in melanoma families with germline CDKN2A mutations. J Invest Dermatol. 2000;11428- 33
PubMedArticle
40.
Brand  RE The diagnosis of pancreatic cancer. Cancer J. 2001;7287- 297
PubMed
41.
Brentnall  TA Cancer surveillance of patients from familial pancreatic cancer kindreds. Med Clin North Am. 2000;84707- 718
PubMedArticle
42.
Brentnall  TABronner  MPByrd  DRHaggitt  RCKimmey  MB Early diagnosis and treatment of pancreatic dysplasia in patients with a family history of pancreatic cancer. Ann Intern Med. 1999;131247- 255
PubMedArticle
43.
Bullock  GJGreen  JLBaron  PL Impact of p16 expression on surgical management of malignant melanoma and pancreatic carcinoma. Am J Surg. 1999;17715- 18
PubMedArticle
44.
Brand  REMatamoros  A Imaging techniques in the evaluation of adenocarcinoma of the pancreas. Dig Dis. 1998;16242- 252
PubMedArticle
45.
Niederau  CGrendell  JH Diagnosis of pancreatic carcinoma: imaging techniques and tumor markers. Pancreas. 1992;766- 86
PubMedArticle
46.
Antillon  MRChang  KJ Endoscopic and endosonography guided fine-needle aspiration. Gastrointest Endosc Clin N Am. 2000;10619- 636
PubMed
47.
Masci  EToti  GMariani  S  et al.  Complications of diagnostic and therapeutic ERCP: a prospective multicenter study. Am J Gastroenterol. 2001;96417- 423
PubMedArticle
48.
Brennan  MF Quadrennial review: pancreatic cancer. J Gastroenterol Hepatol. 2000;15G13- G16
PubMedArticle
49.
Brown  RWBrozo Campagna  LDunn  JKCagle  PT Immunohistochemical identification of tumor markers in metastatic adenocarcinoma: a diagnostic adjunct in the determination of primary site. Am J Clin Pathol. 1997;10712- 19
PubMed
50.
Steinberg  W The clinical utility of the CA 19-9 tumor-associated antigen. Am J Gastroenterol. 1990;85350- 355
PubMed
51.
Cubilla  ALFitzgerald  PJ Morphological lesions associated with human primary invasive nonendocrine pancreas cancer. Cancer Res. 1976;362690- 2698
PubMed
52.
Furukawa  TRyoji  CKobari  MMatsuno  SNagura  HTakahashi  T Varying grades of epithelial atypia in the pancreatic ducts of humans. Arch Pathol Lab Med. 1994;118227- 234
PubMed
53.
Hruban  RHGoggins  MParsons  JKern  SE Progression model for pancreatic cancer. Clin Cancer Res. 2000;62969- 2972
PubMed
54.
Vogelstein  BGearon  ERHamilton  SR  et al.  Genetic alterations during colorectal-tumor development. N Engl J Med. 1988;319525- 532
PubMedArticle
55.
Klimstra  DLongnecker  D K-ras mutations in pancreatic ductal proliferative lesions. Am J Pathol. 1994;1451547- 1548
PubMed
56.
Brat  DJLillemoe  KDYeo  CJWarfield  PBHruban  RH Progression of pancreatic intraductal neoplasias to infiltrating adenocarcinoma of the pancreas. Am J Surg Pathol. 1998;22163- 169
PubMedArticle
57.
Brockie  EAnand  AAlbores-Saavedra  J Progression of atypical ductal hyperplasia/carcinoma in situ of the pancreas to invasive adenocarcinoma. Ann Diagn Pathol. 1998;2286- 292
PubMedArticle
58.
Almoguera  CShibata  DForrester  KMartin  JArnheim  NPerucho  M Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell. 1988;53549- 554
PubMedArticle
59.
Manu  MBuckels  JBramhall  S Molecular technology and pancreatic cancer. Br J Surg. 2000;87840- 853
PubMedArticle
60.
Caldas  CHahn  SAHruban  RH  et al.  Detection of K-ras mutations in the stool of patients with pancreatic adenocarcinoma and pancreatic ductal hyperplasia. Cancer Res. 1994;543568- 3573
PubMed
61.
Mulcahy  HAnker  PLyautey  J  et al.  K-ras mutations in the plasma of pancreatic patients. Clin Cancer Res. 1998;4271- 275
PubMed
62.
Mulcahy  HFarthing  MJG Diagnosis of pancreatico-biliary malignancy: detection of gene mutations in plasma and stool. Ann Oncol. 1999;10 (suppl 4) 114- 117
PubMedArticle
63.
Nakaizumi  AUehara  HTakenaka  A  et al.  Diagnosis of pancreatic cancer by cytology and measurement of oncogene and tumor markers in pure pancreatic juice aspirated by endoscopy. Hepatogastroenterology. 1999;4631- 37
PubMed
64.
Tada  MMata  MKawai  S  et al.  Detection of ras gene mutations in pancreatic juice and peripheral blood of patients with pancreatic adenocarcinoma. Cancer Res. 1993;532472- 2474
PubMed
65.
Wakabayashi  TSawabu  NWatanabe  HMorimoto  HSugioka  GTakita  Y Case reports. Am J Gastroenterol. 1996;911848- 1851
PubMed
66.
Watanabe  HSawabu  NOhta  H  et al.  Identification of K-ras oncogene mutations in the pure pancreatic juice of patients with ductal pancreatic cancers. Jpn J Cancer Res. 1993;84961- 965
PubMedArticle
67.
Yamada  TNakamori  SOhzato  H  et al.  Circulating DNA K-ras mutation in pancreatic adenocarcinoma. Clin Cancer Res. 1998;41527- 1532
PubMed
68.
Caldas  C Biliopancreatic malignancy. Ann Oncol. 1999;10 (suppl 4) 153- 156
PubMedArticle
69.
Hiyama  EKodama  TShinbara  K  et al.  Telomerase activity is detected in pancreatic cancer but not in benign tumors. Cancer Res. 1997;57326- 331
PubMed
70.
Uehara  HNakaizumi  ATatsuta  M  et al.  Diagnosis of pancreatic cancer by detecting telomerase activity in pancreatic juice: comparison with K-ras mutations. Am J Gastroenterol. 1999;942513- 2518
PubMedArticle
Study
August 2003

Pancreatic Carcinoma Surveillance in Patients With Familial Melanoma

Author Affiliations

From the Department of Dermatology and Huntsman Cancer Institute (Drs Florell, Alexander, and Leachman) and the Divisions of Gastroenterology (Dr DiSario) and Oncology (Dr Shami), Department of Internal Medicine, University of Utah (Dr Parker), and the Division of Oncology, Department of Internal Medicine, Salt Lake City Veterans Affairs Medical Center (Dr Shami), Salt Lake City, Utah. The authors have no relevant financial interest in this article.

Arch Dermatol. 2003;139(8):1019-1025. doi:10.1001/archderm.139.8.1019
Abstract

Objective  To determine the optimal methods for pancreatic adenocarcinoma surveillance in high-risk patients with familial melanoma and cyclin-dependent kinase inhibitor 2A (CDKN2A) mutations.

Design  Case report with pedigree analysis and literature review, with an emphasis on guideline development for high-risk kindreds with familial pancreatic adenocarcinoma.

Setting  A university-affiliated familial melanoma research clinic.

Patients  The proband was referred as a participant in a research clinic protocol and was found to carry a germline CDKN2A mutation and have a history of melanoma and pancreatic adenocarcinoma. A total of 179 family members were identified through the Utah Population Database and underwent evaluation for history of melanoma and pancreatic adenocarcinoma.

Intervention/Methods  Comprehensive family history and pedigree analysis performed by means of personal interview, medical record review, and use of cancer registry and population database records. Mutation status was confirmed by results of DNA sequence analysis. Tumor identity was confirmed with immunohistochemical markers.

Main Outcome Measures  Estimated risk for pancreatic adenocarcinoma in a high-risk family with CDKN2A-positive melanoma. Guidelines for surveillance in these families were based on review of the literature.

Results  Sequence analysis confirmed a CDKN2A mutation, and immunohistochemical evaluation confirmed the diagnoses of metastatic melanoma and metastatic pancreatic adenocarcinoma. Pedigree analysis showed an observed-expected ratio of 8.9 to 12.6 for pancreatic adenocarcinoma and 16.4 to 20.8 for melanoma in this family. Guidelines used for surveillance of kindreds at high risk for pancreatic adenocarcinoma were applied to families with CDKN2A melanoma.

Conclusion  Patients with melanoma and a germline CDKN2A mutation should be considered for pancreatic adenocarcinoma surveillance that is based on the most recent published studies.

IT HAS BEEN estimated that approximately 5% to 12% of melanomas occur in the familial setting.1 Genetic linkage studies and molecular analyses have established cyclin-dependent kinase inhibitor 2A (CDKN2A, p16, and INK4a) as the major melanoma susceptibility gene in the familial melanoma syndrome.210 Mutations in the CDKN2A gene allow cells to bypass the G1/S cell cycle checkpoint, leading to uncontrolled cell proliferation and growth.1114 Mutations in the CDKN2A gene are found in approximately 20% to 40% of melanoma-prone families1,2,12 and are associated with the familial atypical multiple mole melanoma syndrome (FAMMM).1517

Growing evidence suggests that CDKN2A mutations may also predispose patients to pancreatic carcinoma.11,1727 A study of Dutch families with melanoma by Vasen et al17 identified a specific 19–base-pair (bp) deletion in exon 2 of the CDKN2A gene, which they have named the p16-Leiden deletion, in 19 families with FAMMM. The second most frequent cancer in these families, after melanoma, was pancreatic carcinoma. The cumulative risk for development of pancreatic cancer in individuals with the p16-Leiden deletion was 17%, with a mean age at diagnosis of 58 years, whereas no pancreatic carcinoma developed in individuals from families with suspected FAMMM without the p16-Leiden deletions. However, families with other CDKN2A mutations were not studied. A study of Dutch FAMMM families by Hille et al23 showed nearly equal mortality rates owing to melanoma and pancreatic cancer in these families. One study by Schutte et al25 showed defects in the Rb/p16 pathway in 98% of pancreatic carcinomas. A recent study published by Lynch et al27 proposed a new FAMMM-pancreatic carcinoma syndrome, because the 2 malignancies are so often seen together in patients with CDKN2A mutations. Lal et al11 have suggested that the diagnosis of malignant melanoma and pancreatic adenocarcinoma in the same patient is evidence enough to virtually prove that the patient has an underlying germline CDKN2A mutation. Those authors recommend that relatives of individuals with these double primary malignancies obtain careful screening for melanoma. Vasen et al17 have also recommended surveillance for pancreatic cancer in families with FAMMM in the setting of a prospective study.

Pancreatic carcinoma is the fourth leading cause of cancer death in the United States.28,29 It has the lowest 5-year survival rate of any cancer.28 Approximately 50% of patients have metastatic disease at diagnosis.28,30 It is difficult to screen for pancreatic carcinoma, and screening tests for the general population are not appropriate owing to an unacceptable rate of false-positive findings.30

We herein present the case of a patient from a kindred with familial melanoma and an established functional germline CDKN2A mutation. He survived malignant melanoma with widespread metastases, but died of metastatic pancreatic adenocarcinoma 25 years after his initial melanoma diagnosis. We reviewed the most recent literature surrounding screening methods for early detection of pancreatic tumors, with the goal of evaluating the role of traditional and more innovative surveillance methods in patients with familial malignant melanoma and CDKN2A mutations.

REPORT OF A CASE

The patient first presented in 1978 at 32 years of age with a clinically atypical melanocytic lesion on the right side of his back. The lesion was excised, and pathological evaluation confirmed superficial spreading malignant melanoma, with a depth of 1.24 mm, or Clark level IV. He underwent a wide local excision 6 months later, and results of pathological evaluation showed no further evidence of melanoma in the surrounding tissue. Fourteen months after his initial diagnosis, at 33 years of age, he presented with painful right axillary lymphadenopathy. Right axillary lymph node dissection was performed, and histological sections revealed metastatic malignant melanoma. One month later, he was referred for local radiation therapy of his right axilla. Staging revealed several pulmonary nodules in the right lung. The patient underwent segmental resection of the right upper, middle, and lower lobes, and pathological analysis confirmed metastatic melanoma. After resection, several pulmonary nodules remained, and new ones appeared within 2 months of surgery. The patient underwent 21 courses of chemotherapy with dacarbazine and dactinomycin (actinomycin D) during the course of 2 years. He had complete regression of metastatic melanoma, with no evidence of residual disease.

Two years after chemotherapy, at 39 years of age, the patient had a new primary melanoma (Clark level I-II) on his left shoulder, which was excised. Another primary melanoma, 0.57 mm in depth (Clark level III), was excised from his left upper back 7 years later, at 46 years of age. Both of these lesions were contiguous with the epidermis, suggesting that they were new primary lesions rather than metastatic in origin. In addition, he was diagnosed as having numerous dysplastic nevi, atypical melanocytic hyperplasia, and benign compound nevi.

At 57 years of age, the patient was enrolled in the Familial Melanoma Research Clinic at the Huntsman Cancer Institute at the University of Utah, Salt Lake City. Sequence analysis of DNA showed that he was heterozygous for a V126D (aspartate substituted for valine at amino acid 126) CDKN2A mutation (Figure 1). He had a family history of melanoma and numerous atypical nevi, as well as pancreatic carcinoma (Figure 2), and was diagnosed as having FAMMM syndrome. This pedigree was evaluated using the familial standardized incidence ratio to establish observed-expected ratios for melanoma and pancreatic cancer (Figure 2).31 Two months later, the patient presented to his primary care physician complaining of chronic low back and abdominal pain. Magnetic resonance imaging showed a 2.4-cm enhancing mass in the right kidney. Computed tomography of the abdomen and pelvis showed a 3.3 × 3.2-cm hypoechoic mass in the right kidney and ascites surrounding the liver and spleen. Results of cytology of a paracentesis specimen were consistent with adenocarcinoma, and results of an immunohistochemistry evaluation were negative for melanoma markers (vimentin, S100, and HMB-45) and positive for mucin (Figure 3). This finding was not consistent with renal cell carcinoma or metastatic melanoma. A colonoscopy was performed, but results of all biopsies were negative. Levels of diagnostic serum tumor markers carcinoembryonic antigen, β-human chorionic gonadotropin, and α-fetoprotein were all within reference range, suggesting that the tumor was less likely of colorectal, hepatic, or germ cell origin. However, the cancer antigen 19-9 (CA 19-9) level was markedly elevated to 17 293 U/mL (reference range, 0-37 U/mL). The CA 19-9 result, in conjunction with the negative results of other studies, led to a presumptive diagnosis of pancreatic adenocarcinoma. Laparoscopic exploration revealed widespread metastases. Tissue from the falciform ligament and omentum were positive for cytokeratin 7, carcinoembryonic antigen, and epithelial membrane antigen, and negative for cytokeratin 20, a pattern consistent with pancreatic carcinoma (Figure 3).3235 The patient was discharged to hospice care following the laparoscopy and died 11 days later.

METHODS
SEQUENCING AND ANALYSIS OF GENOMIC DNA

Genomic DNA was isolated from blood using a commercially available kit (Puregene DNA Isolation Kit; Gentra Systems, Inc, Minneapolis, Minn). Polymerase chain reaction (PCR) products were generated for sequence analysis, including the promoter region and exons 1, 2, and 3 of CDKN2A, spanning the splice junctions. Primers were synthesized by means of the University of Utah DNA/Peptide core facility, Salt Lake City, and the sequences were as follows (5′ to 3′): distal promoter region (forward, 5′-GTGCAACTCTGCTTCTAGAACA -3′; reverse, 5′-GCCAGCAAAGGCGTGTTT-3′); proximal promoter region (forward, 5′-GCCATACTTTCCCTATGACAC -3′; reverse, 5′-GCCCGCACCTCCTCTA-3′); exon 1 (forward, 5′-CACCTCCTCCGAGCACTC-3′; reverse, 5′-CTCCTCATTCCTCTTCCTTGG-3′); exon 2 (forward, 5′-GACGACAGCTCCGCAGAAGTT-3′; reverse, 5′-GCGTGAGCTGAGGCAAGACC-3′); and exon 3 (forward, 5′-GGTAGGGACGGCAAGAGA-3′; reverse, 5′-TGTAATAGGTGCTCAATAAATGTTGACA-3′). Polymerase chain reactions were performed using 0.5µm forward and reverse primers, 1 × PCR buffer (Idaho Technology Inc, Salt Lake City, Utah); 0.25 mM deoxyribonucleoside triphosphates (Takara Bio Inc, Otsu, Japan), 50- to 100-ng genomic DNA template, and 1.0-U Taq DNA polymerase (Fermentas Inc, Hanover, Md) with Taq antibody (BD Biosciences Clontech, Palo Alto, Calif). Cycling conditions included an initial 5-minute incubation at 94°C, followed by 40 cycles of 94°C for 30 seconds of denaturing, 58°C for 30 seconds of annealing, and 72°C for 60 seconds of extension. A final extension period of 5 minutes at 72°C was performed at completion of the 40 cycles. Before sequencing, each sample was treated with exonuclease I and shrimp alkaline phosphatase (EXOSAPIT; USB Corporation, Cleveland, Ohio). Sequencing was performed using the same primers by the University of Utah Sequencing Core Facility with a fluorescent capillary sequencer (3700 ABI; Applied Biosystems, Foster City, Calif).

IMMUNOHISTOCHEMISTRY

Histological analysis and immunohistochemistry were performed as previously described.36,37 Briefly, formalin-fixed, paraffin-embedded tissue sections were deparaffinized in xylene and absolute ethanol, then rehydrated by means of successive immersions in 95% ethanol, 70% ethanol, and distilled water. Immunoperoxidase staining was performed on the Ventana ES instrument (Ventana Medical Systems, Inc, Tucson, Ariz) using the avidin-biotin-peroxidase complex according to manufacturer recommendations. We applied primary antibodies to proteins S100 (DAKO Corporation, Carpinteria, Calif) diluted 1:700, cytokeratin AE1/AE3 (Boehringer Mannheim Biochemicals, Indianapolis, Ind) diluted 1:1400, and Melan-A (DAKO Corporation) diluted 1:20 (heat-induced epitope retrieval was performed before primary antibody incubation). The immunostaining was developed using diaminobenzidine as the chromogen, and samples were counterstained with Mayer hematoxylin. We performed hematoxylin-eosin, mucicarmine, and Wright stains according to standard laboratory protocols.

PEDIGREE ANALYSIS

Pedigree analyses were performed through the use of the Utah Population Database. This database contains computerized genealogies from the Family History Library of the Church of Jesus Christ of Latter-Day Saints, which are linked to statewide records from the Utah Cancer Registry, another population-based database that includes clinical and pathological records on all reportable cancers. Through this database, a 6-generation pedigree containing 179 subjects was constructed and evaluated for a history of melanoma and pancreatic adenocarcinoma. The observed-expected ratio of melanoma and pancreatic carcinoma were calculated using the familial standardized index ratio as reported previously.31

COMMENT

The involvement of CDKN2A in susceptibility to melanoma is now well established. The estimated gene penetrance for melanoma in those with CDKN2A mutations by 80 years of age is 58% to 92%38,39 and is geographically variable.38 After melanoma, pancreatic carcinoma is the cancer most commonly associated with the familial melanoma syndrome and CDKN2A mutations.17,2325,27 Penetrance estimations for pancreatic carcinoma in those with CDKN2A mutations have not yet been well established, but a Dutch study estimated a 17% penetrance by 75 years of age in FAMMM families with the p16-Leiden 19-bp deletion.17 Despite these high penetrance numbers and the fact that 20% to 40% of familial melanoma is associated with CDKN2A mutations,1,2,12 most clinicians take no precautions to prevent this fatal disease.

It is well known that pancreatic cancer is an extremely aggressive tumor, and early detection is exceptionally difficult. Barriers to early detection include absence of symptoms at early stages of disease and the retroperitoneal placement of the pancreas.40 The most common presenting symptoms of pancreatic cancer include chronic epigastric pain radiating to the back, jaundice, weight loss, diarrhea, steatorrhea, and new-onset diabetes or hyperglycemia.28,4042 Once diagnosed, pancreatic cancer is notoriously difficult to treat. It is generally diagnosed after it has metastasized, and patients usually die within 12 months of diagnosis.27,29,30 To date, no known screening method is sensitive and specific enough to screen the asymptomatic general population.30 Experts suggest that surveillance is warranted in high-risk populations, such as those with a family history of pancreatic cancer or melanoma, but optimal screening methods are uncertain.17,27,30,41,43 Although effective strategies have been developed to screen for early detection of breast, prostate, colon, and cervical cancer, the pancreas creates an obstacle for similar screening methods because of the difficulty in visualizing or obtaining tissue from this organ.

In the past, traditional imaging techniques have been the primary focus of research in this area.44,45 The American Gastroenterological Association recommends at-risk patients undergo screening with spiral computed tomography, endoscopic ultrasonography (EUS), and measurement of CA 19-9 level as the initial screening tests.28 More recent work has found EUS and endoscopic retrograde cholangiopancreatography (ERCP) to have sensitivity and specificity values in the lower to middle 90s for diagnosis of pancreatic carcinoma.42,44,46 The major limitation of EUS and ERCP is their invasiveness. Patients require conscious sedation for the procedure and have about a 5% risk for complications, including acute pancreatitis and hemorrhage.46,47 Although these imaging studies appear to be promising for the diagnosis of pancreatic carcinoma, their utility as a screening or surveillance method is uncertain.42 Brentnall41 has suggested an algorithm for surveillance of those at high risk for pancreatic cancer, beginning 10 years before the earliest diagnosis of pancreatic carcinoma in the patient's family or 50 years of age, whichever comes first.

Another promising modality for surveillance is the measurement of tumor markers, which are easily detected in body fluids and tissues. At present, there are no known tumor-specific markers for pancreatic cancer, although CA 19-9 is widely used.48,49 With a cutoff of 37 U/mL, the CA 19-9 level has sensitivity of 81% to 85% and specificity of 81% to 90% in detecting pancreatic adenocarcinoma.45,50 Steinberg50 has shown that CA 19-9 levels greater than 1000 U/mL approach 100% specificity for diagnosing pancreatic cancer. However, in 1 study, serum CA 19-9 and carcinoembryonic antigen levels were not shown to be sensitive enough markers for early detection of premalignant lesions.42 Although measurement of CA 19-9 levels may not be sensitive enough to detect pancreatic dysplasia, changes in CA 19-9 levels over time may be sensitive enough to detect early pancreatic adenocarcinoma, perhaps before the tumor has metastasized or grown large enough to be unresectable. Sensitivity and specificity of 80% to 90%, as estimated for CA 19-9 levels in detection of pancreatic cancer,45,50 may not be adequate for screening in the asymptomatic population. However, in high-risk patients such as those with CDKN2A mutations, these statistics suggest that an annual measurement of this antigen level may be beneficial as surveillance.

To improve screening methods for early detection of pancreatic carcinoma, a better understanding of the molecular and histological pathology involved in progression of this cancer is needed.51,52 A model outlining the progression of pancreatic cancer has recently been introduced by Hruban et al.53 This model was patterned after the genetic progression model for colorectal neoplasia.54 The model proposes that pancreatic cancer progresses from normal ductal epithelium to ductal hyperplasia to invasive ductal adenocarcinoma. The authors use the term pancreatic intraepithelial neoplasia55 to describe this progression from normal epithelium to differing levels of neoplasia. In sporadic pancreatic carcinoma, the progression from level 1 to level 3 disease is often associated with a sequence of genetic alterations, first in K-ras and Her-2/neu, followed by p16 alterations, and finally abnormalities in p53, DPC4, BRCA2, and other tumor suppressor genes.53,56,57 Genetic changes in oncogenes, tumor suppressors, and telomerase are being studied as noninvasive screening tests in individuals at risk for development of pancreatic cancer.30,58,59 Testing of stool, pancreatic juice, and blood for K-ras, p53, p16, and DPC4 mutations or telomerase activity is still in its infancy, but it is hoped that highly sensitive methods such as restriction fragment length polymorphism PCR will soon be available for serological testing.5870 Further study in these areas is warranted before these methods can be used as a surveillance method for pancreatic carcinoma.

CONCLUSIONS

We propose an algorithm to be used for surveillance of patients with familial melanoma patients and known CDKN2A mutations, based on the surveillance program recommended by Brentnall41 in 2000 (Figure 4). Although no screening method has been effective in reducing the mortality rate for sporadic pancreatic cancer, patients with a known CDKN2A mutation are at high risk and surveillance is appropriate in this subpopulation. Confirmed CDKN2A mutations are present in only 20% to 40% of families with familial melanoma,1,2,12 and there is no known or proven correlation between families with non-CDKN2A familial melanoma and increased predisposition to pancreatic cancer. Therefore, we cannot recommend pancreatic cancer surveillance on any member of a kindred with FAMMM without a known CDKN2A mutation. At present, CDKN2A results are obtained primarily through research protocols, making referral to one of these studies important for these family members.

Surveillance should begin 10 years before the age at onset of pancreatic carcinoma in the youngest member of the patient's family who has been diagnosed as having pancreatic carcinoma. If no family history of pancreatic carcinoma is known, surveillance should begin at 50 years of age. Initial screening with EUS is suggested in asymptomatic patients. The annual EUS examination should be performed and interpreted by an individual who is an expert in EUS and diseases of the pancreas. If the EUS finding is abnormal, ERCP will be performed. If the patient is symptomatic or has a history of pancreatitis, alcohol abuse, or cholelithiasis, which can influence the EUS findings, ERCP should be performed initially in addition to the EUS. If suspicious changes are detected on ERCP, total pancreatectomy should be considered. Spiral computed tomography should be considered before surgery to detect large masses or metastases. Frozen sections should be obtained in the operating room and evaluated by a pathologist who is a pancreatic specialist to make a histological diagnosis of pancreatic dysplasia or carcinoma before the pancreatectomy. Such a surveillance program is best performed at a center specializing in the endoscopy, pathology, and surgery of the pancreas.

At present, the CA 19-9 level is not used as a screening method for high-risk patients or those with sporadic disease because of concern regarding insensitivity and lack of specificity in sporadic pancreatic cancer. However, in certain high-risk subsets of patients, annual testing in conjunction with EUS may increase the capacity for early detection. We suggest an annual measurement of the CA 19-9 level. If a patient is found to have a CA 19-9 level near or greater than 37 U/mL or experiences a dramatic increase in the level during a 1-year period, ERCP is suggested. Until K-ras, p53, or DPC4 mutations or telomerase levels (or a combination of these tests) have been validated as screening tools, these are not recommended outside research protocols. In the future, we envision a screening test for patients with familial melanoma and CDKN2A mutations using an annual quantitative serum measurement of CA 19-9, carcinoembryonic antigen, K-ras, or telomerase level to detect early pancreatic neoplasia, much as the prostate-specific antigen level is used to detect prostate cancer. Future research on the cost-benefit ratio and efficacy of these screening recommendations in families with the CDKN2A mutation is planned. If benefit is demonstrated, clinical CDKN2A testing in families with familial melanoma may be warranted.

Back to top
Article Information

Corresponding author and reprints: Sancy A. Leachman, MD, PhD, Hunstman Cancer Institute at the University of Utah, 2000 Circle of Hope, Room 5242, Salt Lake City, UT 84112 (e-mail: sancy.leachman@hci.utah.edu).

Accepted for publication February 18, 2003.

This study was supported by the Huntsman Cancer Foundation and the Huntsman General Clinical Research Center (Salt Lake City); grant MO1 RR00064 from the Salt Lake City General Clinical Research Center Public Health Service; grant SR03CA096429-2 from the National Cancer Institute (Bethesda, Md); and the Utah Cancer Registry, which is funded by contract NCI-CN-67000 from the National Cancer Institute with additional support from the Utah Department of Health and the University of Utah (Salt Lake City).

We thank the Doris Duke Charitable Foundation (New York, NY), Hunstman Cancer Foundation, The Tom C. Matthews Jr Familial Melanoma Research Clinic (Salt Lake City), the Pedigree Population Resource (Salt Lake City), and the following individuals: Jahn Barlow, Thomas Day, Heidi Hanson, Marybeth Hart, MS, Richard Kerber, PhD, Patricia Porter-Gill, and Lisa Wadge, MS, CGC, for their support of and contributions to this manuscript.

References
1.
Goldstein  AMTucker  MA Genetic epidemiology of cutaneous melanoma: a global perspective. Arch Dermatol. 2001;1371493- 1496
PubMedArticle
2.
Piepkorn  MW Genetic basis of susceptibility to melanoma. J Am Acad Dermatol. 1994;311022- 1039
PubMedArticle
3.
Della Ragione  FRusso  GOliva  A  et al.  5′-Deoxy-5′ methylthioadenosine phosphorylase and p16INK4 deficiency in multiple tumor cell lines. Oncogene. 1995;10827- 833
PubMed
4.
Goldstein  AMDracopoli  NCEngelstein  MFrase  MCClark  WHTucker  MA Linkage of cutaneous malignant melanoma/dysplastic nevi to chromosome 9p, and evidence for genetic heterogeneity. Am J Hum Genet. 1994;54489- 496
PubMed
5.
Gruis  NASandkuijl  LAvan der Velden  PABergman  WFrants  RR CDKN2 explains part of the clinical phenotype in Dutch familial atypical multiple-mole melanoma (FAMMM) syndrome families. Melanoma Res. 1995;5169- 177
PubMedArticle
6.
Harland  MMeloni  RGruis  N  et al.  Germline mutations of the CDKN2A gene in UK melanoma families. Hum Mol Genet. 1997;62061- 2067
PubMedArticle
7.
Holland  EABeaton  SCBecker  TM  et al.  Analysis of the p16 gene, CDKN2, in 17 Australian melanoma kindreds. Oncogene. 1995;112289- 2294
PubMed
8.
Hussussian  CJStruewing  JPGoldstein  AM  et al.  Germline p16 mutations in familial melanoma. Nat Genet. 1994;815- 21
PubMedArticle
9.
Ranade  KHussussian  CJSikorski  RS  et al.  Mutations associated with familial melanoma impair p16INK4 function. Nat Genet. 1995;10114- 116
PubMedArticle
10.
Walker  GJHussussian  CJFlores  JF  et al.  Mutations of the CDKN2/p16INK4 gene in Australian melanoma kindreds. Hum Mol Genet. 1995;41845- 1852
PubMedArticle
11.
Lal  GLiu  LHogg  DLassam  NJRedston  MSGallinger  S Patients with both pancreatic adenocarcinoma and melanoma may harbor germline CDKN2A mutations. Genes Chromosomes Cancer. 2000;27358- 361
PubMedArticle
12.
Piepkorn  M Melanoma genetics: an update with focus on the CDKN2A(p16)/ARF tumor suppressors. J Am Acad Dermatol. 2000;42705- 722
PubMedArticle
13.
Ruas  MPeters  G The p16INK4a/CDKN2A tumor suppressor and its relatives. Biochim Biophys Acta. 1998;1378F115- F177
PubMed
14.
Serrano  MHannon  GJBeach  D A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature. 1993;366704- 707
PubMedArticle
15.
Clark  WHReimer  RRGreene  MAinsworth  AMMastrangelo  MJ Origin of familial malignant melanomas from heritable melanocytic lesions: "the B-K mole syndrome." Arch Dermatol. 1978;114732- 738
PubMedArticle
16.
Newton-Bishop  JABataille  VPinney  EBishop  DT Family studies in melanoma: identification of the atypical mole syndrome (AMS) phenotype. Melanoma Res. 1994;4199- 206
PubMedArticle
17.
Vasen  HFAGruis  NAFrantis  RRvan der Velden  PAHille  ETMBerman  W Risk of developing pancreatic cancer in families with familial atypical multiple mole melanoma associated with a specific 19 deletion of p16 (p16-Leiden). Int J Cancer. 2000;87809- 811
PubMedArticle
18.
Bergman  WWatson  Pde Jong  JLynch  HTFusaro  RM Systemic cancer and the FAMMM syndrome. Br J Cancer. 1990;61932- 936
PubMedArticle
19.
Bergman  WGruis  N Familial melanoma and pancreatic cancer [letter]. N Engl J Med. 1996;334471- 472
PubMed
20.
Borg  ASandberg  TNilsson  K  et al.  High frequency of multiple melanomas and breast and pancreas carcinomas in CDKN2A mutation–positive melanoma families. J Natl Cancer Inst. 2000;921260- 1266
PubMedArticle
21.
Ghiorzo  PCiotti  PMartelli  M  et al.  Characterization of ligurian melanoma families and risk of occurrence of other neoplasia. Int J Cancer. 1999;83441- 448
PubMedArticle
22.
Goldstein  AMFraser  MCStruewing  JP  et al.  Increased risk of pancreatic cancer in melanoma-prone kindreds with p16INK4 mutations. N Engl J Med. 1995;333970- 974
PubMedArticle
23.
Hille  ETMvan Duijn  EGruis  NARosendaal  FRBergman  WVandenbroucke  JP Excess cancer mortality in six Dutch pedigrees with the familial atypical multiple mole-melanoma syndrome from 1830 to 1994. J Invest Dermatol. 1998;110788- 792
PubMedArticle
24.
Lal  GLiu  GSchmocker  G  et al.  Inherited predisposition to pancreatic adenocarcinoma. Cancer Res. 2000;60409- 416
PubMed
25.
Schutte  MHruban  RHGeradts  J  et al.  Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas. Cancer Res. 1997;573126- 3130
PubMed
26.
Whelan  AJBartsch  DGoodfellow  PJ Brief report: a familial syndrome of pancreatic cancer and melanoma with a mutation in the CDKN2 tumor-suppressor gene. N Engl J Med. 1995;333975- 977
PubMedArticle
27.
Lynch  HTBrand  RBHogg  D  et al.  Phenotypic variation in eight extended CKDN2A germline mutation familial atypical mole melanoma-pancreatic carcinoma–prone families. Cancer. 2002;9484- 96
PubMedArticle
28.
Not Available, American Gastroenterological Association medical position statement. Gastroenterology. 1999;1171463- 1484
PubMedArticle
29.
Jemal  AThomas  AMurray  TThun  M Cancer statistics 2002. CA Cancer J Clin. 2002;5223- 47
PubMedArticle
30.
Hruban  RHCanto  MIYeo  CJ Prevention of pancreatic cancer and strategies for management of familial pancreatic cancer. Dig Dis. 2001;1976- 84
PubMedArticle
31.
Kerber  RA Method for calculating risk associated with family history of a disease. Genet Epidemiol. 1995;12291- 301
PubMedArticle
32.
Chu  PWu  EWeiss  L Cytokeratin 7 and cytokeratin 20 expression in epithelial neoplasms: a survey of 435 cases. Mod Pathol. 2000;13962- 972
PubMedArticle
33.
Ichihara  TNomoto  STakeda  S  et al.  Clinical usefulness of the immunostaining of the tumor markers in pancreatic cancer. Hepatogastroenterology. 2001;48939- 943
PubMed
34.
Tot  T Adenocarcinomas metastatic to the liver. Cancer. 1999;85171- 177
PubMedArticle
35.
Tot  T The value of cytokeratins 20 and 7 in discriminating metastatic adenocarcinomas from pleural mesotheliomas. Cancer. 2001;922727- 2732
PubMedArticle
36.
Florell  SRCoffin  CMHolden  JA  et al.  Preservation of RNA for functional genomic studies: a multidisciplinary tumor bank protocol. Mod Pathol. 2001;14116- 128
PubMedArticle
37.
Florell  SRZone  JJGerwels  JW Basal cell carcinomas are populated by melanocytes and Langerhans cells. Am J Dermatopathol. 2001;2324- 28
PubMedArticle
38.
Bishop  DTDemenais  FGoldstein  A  et al.  Geographical variation in the penetrance of CDKN2A mutations for melanoma. J Natl Cancer Inst. 2002;94894- 903
PubMedArticle
39.
Newton-Bishop  JAWachsmuth  RCHarland  M  et al.  Genotype/phenotype and penetrance studies in melanoma families with germline CDKN2A mutations. J Invest Dermatol. 2000;11428- 33
PubMedArticle
40.
Brand  RE The diagnosis of pancreatic cancer. Cancer J. 2001;7287- 297
PubMed
41.
Brentnall  TA Cancer surveillance of patients from familial pancreatic cancer kindreds. Med Clin North Am. 2000;84707- 718
PubMedArticle
42.
Brentnall  TABronner  MPByrd  DRHaggitt  RCKimmey  MB Early diagnosis and treatment of pancreatic dysplasia in patients with a family history of pancreatic cancer. Ann Intern Med. 1999;131247- 255
PubMedArticle
43.
Bullock  GJGreen  JLBaron  PL Impact of p16 expression on surgical management of malignant melanoma and pancreatic carcinoma. Am J Surg. 1999;17715- 18
PubMedArticle
44.
Brand  REMatamoros  A Imaging techniques in the evaluation of adenocarcinoma of the pancreas. Dig Dis. 1998;16242- 252
PubMedArticle
45.
Niederau  CGrendell  JH Diagnosis of pancreatic carcinoma: imaging techniques and tumor markers. Pancreas. 1992;766- 86
PubMedArticle
46.
Antillon  MRChang  KJ Endoscopic and endosonography guided fine-needle aspiration. Gastrointest Endosc Clin N Am. 2000;10619- 636
PubMed
47.
Masci  EToti  GMariani  S  et al.  Complications of diagnostic and therapeutic ERCP: a prospective multicenter study. Am J Gastroenterol. 2001;96417- 423
PubMedArticle
48.
Brennan  MF Quadrennial review: pancreatic cancer. J Gastroenterol Hepatol. 2000;15G13- G16
PubMedArticle
49.
Brown  RWBrozo Campagna  LDunn  JKCagle  PT Immunohistochemical identification of tumor markers in metastatic adenocarcinoma: a diagnostic adjunct in the determination of primary site. Am J Clin Pathol. 1997;10712- 19
PubMed
50.
Steinberg  W The clinical utility of the CA 19-9 tumor-associated antigen. Am J Gastroenterol. 1990;85350- 355
PubMed
51.
Cubilla  ALFitzgerald  PJ Morphological lesions associated with human primary invasive nonendocrine pancreas cancer. Cancer Res. 1976;362690- 2698
PubMed
52.
Furukawa  TRyoji  CKobari  MMatsuno  SNagura  HTakahashi  T Varying grades of epithelial atypia in the pancreatic ducts of humans. Arch Pathol Lab Med. 1994;118227- 234
PubMed
53.
Hruban  RHGoggins  MParsons  JKern  SE Progression model for pancreatic cancer. Clin Cancer Res. 2000;62969- 2972
PubMed
54.
Vogelstein  BGearon  ERHamilton  SR  et al.  Genetic alterations during colorectal-tumor development. N Engl J Med. 1988;319525- 532
PubMedArticle
55.
Klimstra  DLongnecker  D K-ras mutations in pancreatic ductal proliferative lesions. Am J Pathol. 1994;1451547- 1548
PubMed
56.
Brat  DJLillemoe  KDYeo  CJWarfield  PBHruban  RH Progression of pancreatic intraductal neoplasias to infiltrating adenocarcinoma of the pancreas. Am J Surg Pathol. 1998;22163- 169
PubMedArticle
57.
Brockie  EAnand  AAlbores-Saavedra  J Progression of atypical ductal hyperplasia/carcinoma in situ of the pancreas to invasive adenocarcinoma. Ann Diagn Pathol. 1998;2286- 292
PubMedArticle
58.
Almoguera  CShibata  DForrester  KMartin  JArnheim  NPerucho  M Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell. 1988;53549- 554
PubMedArticle
59.
Manu  MBuckels  JBramhall  S Molecular technology and pancreatic cancer. Br J Surg. 2000;87840- 853
PubMedArticle
60.
Caldas  CHahn  SAHruban  RH  et al.  Detection of K-ras mutations in the stool of patients with pancreatic adenocarcinoma and pancreatic ductal hyperplasia. Cancer Res. 1994;543568- 3573
PubMed
61.
Mulcahy  HAnker  PLyautey  J  et al.  K-ras mutations in the plasma of pancreatic patients. Clin Cancer Res. 1998;4271- 275
PubMed
62.
Mulcahy  HFarthing  MJG Diagnosis of pancreatico-biliary malignancy: detection of gene mutations in plasma and stool. Ann Oncol. 1999;10 (suppl 4) 114- 117
PubMedArticle
63.
Nakaizumi  AUehara  HTakenaka  A  et al.  Diagnosis of pancreatic cancer by cytology and measurement of oncogene and tumor markers in pure pancreatic juice aspirated by endoscopy. Hepatogastroenterology. 1999;4631- 37
PubMed
64.
Tada  MMata  MKawai  S  et al.  Detection of ras gene mutations in pancreatic juice and peripheral blood of patients with pancreatic adenocarcinoma. Cancer Res. 1993;532472- 2474
PubMed
65.
Wakabayashi  TSawabu  NWatanabe  HMorimoto  HSugioka  GTakita  Y Case reports. Am J Gastroenterol. 1996;911848- 1851
PubMed
66.
Watanabe  HSawabu  NOhta  H  et al.  Identification of K-ras oncogene mutations in the pure pancreatic juice of patients with ductal pancreatic cancers. Jpn J Cancer Res. 1993;84961- 965
PubMedArticle
67.
Yamada  TNakamori  SOhzato  H  et al.  Circulating DNA K-ras mutation in pancreatic adenocarcinoma. Clin Cancer Res. 1998;41527- 1532
PubMed
68.
Caldas  C Biliopancreatic malignancy. Ann Oncol. 1999;10 (suppl 4) 153- 156
PubMedArticle
69.
Hiyama  EKodama  TShinbara  K  et al.  Telomerase activity is detected in pancreatic cancer but not in benign tumors. Cancer Res. 1997;57326- 331
PubMed
70.
Uehara  HNakaizumi  ATatsuta  M  et al.  Diagnosis of pancreatic cancer by detecting telomerase activity in pancreatic juice: comparison with K-ras mutations. Am J Gastroenterol. 1999;942513- 2518
PubMedArticle
×