Prolonged Survival of a Patient Affected by Pancreatic Adenocarcinoma with Massive Lymphocyte and Dendritic Cell Infiltration after Interleukin-2 Immunotherapy. Report of a Case
Restricted accessResearch articleFirst published online May, 2008
Prolonged Survival of a Patient Affected by Pancreatic Adenocarcinoma with Massive Lymphocyte and Dendritic Cell Infiltration after Interleukin-2 Immunotherapy. Report of a Case
Several studies have shown that there is a paucity of immune cells within the stroma of pancreatic adenocarcinoma, a very aggressive cancer with a median survival of about 18 months. A 65-year-old man presented with jaundice. Abdominal ultrasound revealed intra- and extrahepatic bile duct dilatation and a 45-mm diameter hypoechoic solid mass within the pancreatic head; a computed tomography scan excluded vascular infiltration and metastatic lesions. The patient received immunotherapy consisting of 6,000,000 IU human recombinant interleukin-2 administered subcutaneously twice a day for 3 consecutive days. Thirty-six hours after the last dose, he underwent a pylorus-preserving pancreatoduodenectomy. Because of the presence of high-grade dysplasia detected by intraoperative histological examination of a distal section, a spleen preserving total pancreatectomy was performed. The postoperative course was uneventful. The patient died 32 months after surgery because of local recurrence. Histopathology showed G3 pancreatic ductal adenocarcinoma infiltrating the anterior and posterior peripancreatic tissue, duodenal wall and intrapancreatic common bile duct, with sarcoma-like foci and a component of intraductal tumor involving the common bile duct. In the distal pancreas, widespread foci of pancreatic intraepithelial neoplasia (PanIN2-3) were found. The Ki-67 proliferation index was 16%. TNM staging was pT3 pN1 R1. Sections were immunostained for the T-lymphocyte marker CD3 and for the dendritic cell marker CD1a. Intratumoral infiltration was high for CD1a+ cells and mild for CD3+ cells. Preoperative immunotherapy with interleukin-2 may contribute to massive stromal infiltration of immune cells in pancreatic adenocarcinoma. This may prolong the survival even in the presence of negative prognostic factors (age >65 years, tumor diameter >20 mm, R1, tumor grade G3).
IsajiS., KawaradaY., UemotoS.: Classification of pancreatic cancer. Comparison of Japanese and UICC classification.Pancreas, 28: 231–234, 2004.
3.
ConlonK.C., KlimstraD.S., BrennanM.F.: Long-term survival after curative resection for pancreatic ductal adenocarcinoma. Clinicopathologic analysis of 5-years survivors.Ann Surg, 223: 273–279, 1996.
4.
EvansD.B., RichT.A., ByrdD.R., AmesF.C.: Adenocarcinoma of the pancreas: current management of resectable and locally advanced disease.South Med J, 84: 566–570, 1991.
5.
SohnT., YeoC.J., CameronJ.L., KoniarisL., KaushalS., AbramsR.A., SauterP.K., ColemanJ., HrubanR.H., LillemoeK.D.: Resected adenocarcinoma of the pancreas. 616 patients: results, outcomes and prognostic indicators.J Gastrointest Surg, 4: 567–579, 2000.
6.
VerbekeC.S., LeitchD., MenonK.V., McMahonM.J., GuillouP.J., AnthoneyA.: Redefining the R1 resection in pancreatic cancer.Br J Surg, 93: 1232–1237, 2006.
7.
YeoC.J., CameronJ.L., SohnT.A., LillemoeK.D., PittH.A., TalaminiM.A., HrubanR.H., OrdS.E., SauterP.K., ColemanJ., ZahurakM.L., GrochowL.B., AbramsR.A.: Six hundred fifty consecutive pancreatoduodenectomies in the 1990s: pathology, complications and outcomes.Ann Surg, 226: 248–257, 1997.
8.
MocellinS., RossiC.R., LiseM., MarincolaF.M.: Adjuvant immunotherapy for solid tumors: from promise to clinical application.Cancer Immunol Immunother, 51: 583–595, 2002.
9.
BremersA.J.A., ParmianiG.: Immunology and immunotherapy of human cancer: present concept and clinical developments.Crit Rev Oncol Hematol, 34: 1–25, 2000.
10.
FriessH., GrassmannM., BuchlerM.W.: Adjuvant therapy of pancreatic cancer using monoclonal antibodies and immune response modifiers.Int J Pancreatol, 21: 43–52, 1997.
11.
RosenbergS.A., LotzeM.T., YangJ.C., AebersoldP.M., LinehanW.M., SeippC.A., WhiteD.E.: Experience with the use of high-dose interleukin-2 in the treatment of 652 cancer patients.Ann Surg, 210: 474–485, 1989.
12.
BukowskiR.M., OlenckiZ.T., WangQ., PeereboomD., BuddG.T., ElsonP., SandstromK., TuasonL., RaymanP., TubbsR., McLainD., KleinE., NovickA., FinkeJ.: Phase II trial of interleukin-2 and interferon-alpha in patients with renal cell carcinoma: clinical results and immunologic correlates of response.J Immunother, 20: 301–311, 1997.
13.
KrastevZ., KoltchakovV., TomovB., KotenJ.W.: Non-melanoma and non-renal cel carcinoma malignancies treated with interleukin-2.Hepatogastroenterology, 50: 1006–1016, 2003.
14.
Abdel-WahabM., El ShennawyF., AghaS., RagabE., FathiO., SultanA., ElghawalbyN., EzzatF.: Evaluation of cell mediated immunity in advanced pancreatic carcinoma before and after treatment with interleukin-2 (IL-2).Hepatogastroenterology,46s: 1293–1296, 1999.
15.
LygidakisN.J., SgourakisG., GeorgiaD., VlachosL., RaptisS.: Regional targeting chemoimmunotherapy in patients undergoing pancreatic resections in an advanced stage of their disease: a prospective randomized study.Ann Surg, 236: 806–813, 2002.
16.
FischerJ.R., SchindelM., SteinN., LahmH., GallatiH., KrammerP.H., DringsP.: Selective suppression of cytokine secretion in patient with small-lung cancer.Ann Oncol, 6: 921–926, 1995.
17.
YoshinoI., YanoT., MurataM., IshidaT., SugimachiK., KimuraG., NomotoK.: Tumor-reactive T-cells accumulate in lung cancer tissues but fail to respond due to tumor cell derived factor.Cancer Res, 52: 775–781, 1992.
18.
SchmielauJ., FinnO.J.: Activated granulocytes and granulocyte-derived hydrogen peroxide are the underlying mechanism of suppression of T-cell function in advanced cancer patients.Cancer Res, 61: 4756–4760, 2001.
19.
NielsenH.J., HansenU., ChristensenI.J., ReimertC.M., BrunnerN., MoesgaardF.: Independent prognostic value of eosinophil and mast cell infiltration in colorectal cancer tissue.J Pathol, 189: 487–495, 1999.
20.
NagtegaalI.D., MarijnenC.A., KranenbargE.K., Mulder-StapelA., HermansJ., van de VeldeC.J., van KriekenJ.H.: Local and distant recurrences in rectal cancer patients are predicted by the nonspecific immune response; specific immune response has only a systemic effect – a histopathological and immunohistochemical study.BMC Cancer, 1: 7, 2001.
21.
DallalR.M., ChristakosP., LeeK., EgawaS., SonY.I., LotzeM.T.: Paucity of dendritic cells in pancreatic cancer.Surgery, 131: 135–138, 2002.
22.
von BernstorffW., VossM., FreichelS., SchmidA., VogelI., JohnkC., Henne-BrunsD., KremerB., KalthoffH.: Systemic and local immunosuppression in pancreatic cancer patients.Clin Cancer Res, 7: 925s–932s, 2001.
23.
GarbeA.I., VermeerB., GamrekelashviliJ., von WasielewskiR., GretenF.R., WestendorfA.M., BuerJ., SchmidR.M., MannsM.P., KorangyF., GretenT.F.: Genetically induced pancreatic adenocarcinoma is highly immunogenic and causes spontaneous tumor-specific immune responses.Cancer Res, 66: 508–516, 2006.
24.
GranssR., HanahanD.: Tumor microenvironment can restrict the effectiveness of activated antitumor lymphocytes.Cancer Res, 58: 4673–4681, 1998.
25.
OtahalP., SchellT.D., HutchinsonS.C., KnowlesB.B., TevethiaS.S.: Early immunization induces persistent tumor-infiltrating CD8+T cells against an immunodominant epitope and promotes lifelong control of pancreatic tumor progression in SV40 tumor antigen transgenic mice.J Immunol, 177: 3089–3099, 2006.
26.
RyschichE., NotzelT., HinzU., AutschbachF., FergusonJ., SimonI., WeitzJ., FrohlichB., KlarE., BuchlerM.W., SchmidtJ.: Control of T-cell-mediated response by HLA class I in human pancreatic carcinoma.Clin Cancer Res, 11: 498–504, 2005.
27.
AbeM., KondoS., HiranoS., AmboY., TanakaE., MorikawaT., OkushibaS., KatohH.: Long-term survival after radical resection of advanced pancreatic cancer: a case report with special reference to CD8+ T-cell infiltration.Int J Gastrointest Cancer, 33: 107–110, 2003.
28.
KlinkenbijlJ.H., JeekelJ., SahmoudT., van PelR., CouvreurM.L., VeenhofC.H., ArnaudJ.P., GonzalezD.G., de WitL.T., HennipmanA., WilsJ.: Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC Gastrointestinal Tract Cancer Cooperative Group.Ann Surg, 230: 776–784, 1999.
29.
NeoptolemosJ.P., StockenD.D., FriessH., BassiC., DunnJ.A., HickeyH., BegerH., Fernandez-CruzL., DervenisC., LacaineF., FalconiM., PederzoliP., PapA., SpoonerD., KerrD.J., BuchlerM.W., European Study Group for Pancreatic Cancer: A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer.N Engl J Med, 350: 1200–1210, 2004.
30.
NeoptolemosJ.P., StockenD.D., DunnJ.A., AlmondJ., BegerH.G., PederzoliP., BassiC., DervenisC., Fernandez-CruzL., LacaineF., BuckelsJ., DeakinM., AdabF.A., SuttonR., ImrieC., IhseI., TihanyiT., OlahA., PedrazzoliS., SpoonerD., KerrD.J., FriessH., BuchlerM.W., European Study Group for Pancreatic Cancer: Influence of resection margins on survival for patients with pancreatic cancer treated by adjuvant chemoradiation and/or chemotherapy in the ESPAC-1 randomized controlled trial.Ann Surg, 234: 758–768, 2001.
31.
BossetJ.F., PavyJ.J., GilletM., MantionG., PelissierE., SchraubS.: Conventional external irradiation alone as adjuvant treatment in resectable pancreatic cancer: results of a prospective study.Radiother Oncol, 24: 191–194, 1992.
32.
KuhlmannK.F., De CastroS.M., WesselingJ.G., ten KateF.J., OfferhausG.J., BuschO.R., van GulikT.M., ObertopH., GoumaD.J.: Surgical treatment of pancreatic adenocarcinoma; actual survival and prognostic factors in 343 patients.Eur J Cancer, 40: 549–558, 2004.
