case report granulomatous pancreatitis in a patient with...

Case ReportGranulomatous Pancreatitis in a Patient with Acute ManifestedInsulin-Dependent Diabetes Mellitus

Vaacuteclav Mandys1 Michal Kheck2 and Michal Andjl3

1 Department of Pathology Third Faculty of Medicine Charles University in Prague 100 00 Prague 10 Czech Republic2 Department of Pathology Regional Hospital Jihlava 586 33 Jihlava Czech Republic3 Second Department of Internal Medicine Third Faculty of Medicine Charles University in Prague 100 00 Prague Czech Republic

Correspondence should be addressed to Vaclav Mandys vaclavmandysfnkvcz

Received 6 January 2014 Accepted 27 January 2014 Published 5 March 2014

Academic Editors D Jain J S Khurana M M Picken and T Strecker

Copyright copy 2014 Vaclav Mandys et alThis is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Isolated granulomatous noncaseating pancreatitis is a rare condition exceptionally described in human populationWe demonstratea case of the a 71-years-old female patient suffering from recent diabetes mellitus generalized atherosclerosis and hypertensionwho died due to pulmonary embolism and terminal bronchopneumonia Lipomatosis of pancreatic tissue was observed duringthe postmortem examination Histological examination of pancreatic tissue discoveredmultiple small noncaseating epithelioid celland giant cell granulomas partly replacing the islets of Langerhans To our knowledge our case represents the first description ofnoninfectious granulomatous pancreatitis associated with acute manifested insulin-dependent diabetes mellitus

1 Introduction

Noncaseating granulomatous inflammation confined to thepancreas has been only exceptionally described in humanpatients Infections like tuberculosis and syphilis exogenousnoxes autoimmunity and systemic granulomatous diseasesare the most frequent causes of granuloma formation withinthe pancreatic tissue [1] Abdominal pain or epigastric dis-comfort diarrhoea weight loss and obstructive jaundiceare listed among the clinical symptoms of granulomatouspancreatitis [1ndash3] We report a case of a patient who clinicallypresented with acute manifested diabetes mellitus associatedwith isolated granulomatous pancreatitis discovered in thepostmortem examination and we present a review of theavailable literature

2 Clinical History

A 71-year-old obese woman was admitted with the recentonset of diabetes mellitus manifested as hyperglycaemicketoacidotic precoma The past medical history was unre-markable Recently arterial hypertension was discoveredHer body weight was 110 kg BMI 38 The plasma glucose

level ranged from 31 to 151mmolL The patient was treatedwith intensified insulin regime The status of the patient wascomplicated by intermittent fever and several antibiotics wererepeatedly administered Terminally clinical signs of septicshock and multiorgan failure appeared and the patient diedPostmortem examination performed 11 hours after deathdiscovered signs of septic shock with activation of spleenpulp and terminal bronchopneumoniaThromboemboli werefound in several peripheral branches of the pulmonary arteryHypertrophy of the heart (545 g) predominantly of theleft ventricle was also observed The pancreas showed amacroscopically lobular arrangement and lipomatosis othermacroscopic changes were not visible Lungs thoracic lymphnodes and other organs did not show any changes corre-sponding with tuberculous process or sarcoidosis

3 Materials and Methods

Five representative tissue samples of pancreatic tissue takenfrom head body and tail were fixed with 10 formalin androutinely embedded in paraffin Five-120583m-thick sections were

Hindawi Publishing CorporationCase Reports in PathologyVolume 2014 Article ID 615426 4 pageshttpdxdoiorg1011552014615426

2 Case Reports in Pathology

Table 1 Antibodies and their dilutions used in the study

Antibody Source Supplier Dilution

Anti-insulin Mouse monoclonal Diagnostic Biosystems 1 50clone E2E3

Anti-CD45R0 Mouse monoclonal DAKO Cytomation 1 200clone UCHL 1

Anti-CD20cy Mouse monoclonal DAKO Cytomation 1 100clone L26

Anti-alpha-1 Mouse monoclonal Acris Antibodies 1 400Antichymotrypsin clone ACT14C7

Anti-CD68 Mouse monoclonal DAKO Cytomation 1 100clone PG-M1

Antichromogranin A Rabbit polyclonal DAKO Cytomation 1 600

(a) (b)

Figure 1 Focal inflammatory infiltrates within the pancreatic parenchyma Haematoxylin and eosin times100 (a) Dispersed granulomas formedpredominantly of epithelioid cells Haematoxylin and eosin times40 (b)

stained with haematoxylin and eosin and by immunohis-tochemical methods using N-Histofine Immunohistochem-ical staining reagent (Nichirei Biosciences Japan) and 3-31015840diaminobenzidine as a chromogen to visualize the reactionThe list of antibodies including manufacturers and thedilutions used is introduced in Table 1

4 Results

Microscopic examination of pancreatic tissue discovered anincreased amount of lipomatous tissue within the pancre-atic lobules Irregular inflammatory infiltrates of a vari-able density composed predominantly of small lymphocytesand sparse neutrophilic and eosinophilic granulocytes werealso observed (Figure 1(a)) Multiple dispersed small (upto 500120583m) noncaseating epithelioid granulomas with giantcells without Schaumann bodies were present within thepancreatic lobules (Figures 1(b) and 2) Pancreatic islets werenot found Other organs examined histologically that islungs kidneys and liver did not display any granulomatouschanges

Immunohistological examination showed strong immu-noreactivity of macrophages forming the granulomas for

CD68 (Figure 2) and 120572-1 antichymotrypsin Inflammatoryinfiltrates were composed predominantly of CD45R0 positivesmall T-lymphocytes and scattered CD20 positive small Bcells Immunohistological detection of markers of neuroen-docrine differentiation (chromogranin A synaptophysin)and pancreatic hormones (insulin glucagon) verified theoriginal microscopic finding of absence of islets of Langer-hans (Figure 3)

5 Discussion

Granulomatous pancreatitis is a rare condition infrequentlydescribed in infectious diseases like tuberculosis or syphilisand in systemic inflammations Pancreatic tuberculosis isclinically nonspecific Radiological findings can resemble theneoplastic process or chronic inflammation Morphologi-cally it is characterized by caseating granulomas caseousnecrosis can be observed even in fine needle aspirationcytology [4 5] Syphilitic pancreatitis is an acquired diseaseextremely rare It is manifested in the tertiary syphilisClinically jaundice vague epigastric discomfort diarrhoeaand fatigue can appear In the microscopic examination

Case Reports in Pathology 3

Figure 2 Epithelioid and giant cell granuloma Haematoxylin andeosin times200 Inset immunohistological detection of CD68 (B)

Figure 3 Absence of islets of Langerhans in the pancreatic tissueImmunohistological detection of insulin times40 Inset density of isletsof Langerhans in normal (control) pancreatic tissue

apart from noncaseating granulomas vasculitis can also beobserved [1 2]

Noninfectious granulomatous pancreatitis can be ob-served in patients with systemic granulomatous diseasesIn sarcoidosis pancreatic involvement is rare Clinically itis usually manifested as a mass resembling neoplasia [6ndash9] Exceptionally pancreatic sarcoidosis can be manifestedby hypercalcemic pancreatitis [10] Acute pancreatitis anddiabetes mellitus have been also described in individual casesof pancreatic sarcoidosis [11] The microscopic picture ischaracterized by noncaseating giant cell granulomas withoutaccompanying lymphocytic reaction Schaumann bodiesshell-like lamellated calcifications are present in the giantmultinuclear cells [1]

Focal granulomatous inflammation of pancreas has beendescribed inCrohnrsquos disease Granulomaswere noncaseatingcontained numerous giant cells and caused destruction ofpancreatic tissue Obstruction of the common bile duct clin-ically manifested with symptoms of extrahepatic cholestasiswas present as a complication of this inflammatory process[12] Foreign body (suture) granulomas can appear especiallyin the peripancreatic tissue as a consequence of prior surgeryThese granulomas are typically composed of multinucleateor even polynucleate cells containing foreign birefringentmaterial within the cytoplasm [1] Exceptionally granuloma-tous reaction is oriented to arteries Isolated granulomatous

arteritis can lead either to complete obliteration of the vesselor to thickening of fibrotic intima andnarrowing of the lumen[1] Granulomatous inflammation with foamy lipid-ladenmacrophages was observed in several cases of granulomatouspancreatitis and in experimentally induced insulitis in miceimmunized with purified porcine insulin [1 13]

Epithelioid cell granulomas usually in ductulocentriclocation have been rarely described in histological specimensof autoimmune pancreatitis (AP) The majority of patientswere presented by the obstructive jaundice weight lossand abdominal pain Other autoimmune disorders likesclerosing cholangitis or interstitial pneumonia can appearin patients with AP Histologically AP is characterized bydense lymphoplasmacytic infiltrates and secondary fibrosiswithin the pancreatic tissue Inflammation frequently dis-plays a patchy collar arrangement around both small andlarge interlobular ducts and periphlebitis and obliterativephlebitis is invariably observed [14] It seems likely somepreviously described cases of isolated [3] or cryptogenic [1]granulomatous pancreatitis fulfill the diagnostic criteria forAP and clinically also correspond with this disorder On theother hand the histological picture of our case differs fromthe cardinal diagnostic features of AP

Diabetes mellitus in adults is predominantly of type 2Much less frequently type 1 diabetes and latent autoimmunediabetes (LADA) can appear in adult patients [15] Diabetesof the patient described in our report was originally clinicallyclassified as LADA however ketoacidotic manifestation ofthe disease and requirement of urgent insulin treatmentsuggest acute manifested insulin-dependent diabetes melli-tus corresponding with ketosis-prone diabetes (KPD) [16]Granulomatous inflammation combined with disappearanceof the islets has not been described so far either in patientsdisplaying characteristics of LADAor classical type 1 diabetesGranulomatous lesions in the pancreas connected with dia-betes were described under the experimental conditions inrats [17] and in one case of pancreatic sarcoidosis [11]

Our recent finding suggests that granulomatous pan-creatitis is a possible underlying cause of diabetes mellitusand urges the microscopic examination of pancreatic tissueobtained during the post mortem examination of patientswho died with signs and symptoms of recently manifesteddiabetes mellitus

Conflict of Interests

The authors declare that they have no conflict of interests

Acknowledgments

This work was supported by the research Project PRVOUKmdashOncology P27 awarded by Charles University in Prague andtechnically by the Project OPPK no CZ216310024024awarded by the European Regional Development Fund(Prague amp EU We invest for your future)


References

[1] J Sturmer andV Becker ldquoGranulomatous pancreatitis granulo-mas in chronic pancreatitisrdquoVirchows Archiv vol 410 no 4 pp327ndash338 1987

[2] W G Choi CW Lee H J Park et al ldquoA case of granulomatouspancreatitis caused by syphilisrdquoKorean Journal of Medicine vol52 pp 696ndash701 1997

[3] A R Essop J Posen I Segal and D Pantanowitz ldquoIsolatedgranulomatous pancreatitisrdquo Journal of Clinical Gastroenterol-ogy vol 6 no 1 pp 61ndash64 1984

[4] C S Pramesh A A Heroor P J Shukla P M Jagannath andL J De Souza ldquoPancreatic tuberculosisrdquo Tropical Gastroenterol-ogy vol 23 no 3 pp 142ndash143 2002

[5] S Hari A Seith D N Srivastava G Makharia and S PalldquoIsolated tuberculosis of the pancreas diagnosed with needleaspiration a case report and review of the literaturerdquo TropicalGastroenterology vol 26 no 3 pp 141ndash143 2005

[6] N V Adsay O Basturk D S Klimstra and G KloppelldquoPancreatic pseudotumors non-neoplastic solid lesions of thepancreas that clinically mimic pancreas cancerrdquo Seminars in Di-agnostic Pathology vol 21 no 4 pp 260ndash267 2004

[7] M CaceresM S Sabbaghian R Braud SWilks andM BoyleldquoPancreatic sarcoidosis unusual presentation resembling a pe-riampullary malignancyrdquo Current Surgery vol 63 no 3 pp179ndash185 2006

[8] M Shukla M F Hassan V Toor J Kaur C Solomon and HCohen ldquoSymptomatic pancreatic sarcoidosis case report andreview of literaturerdquo Journal of the Pancreas vol 8 no 6 pp770ndash774 2007

[9] A L Mayne Ahmad j M Loughrey and M A Taylor ldquoSarcoi-dosis of the pancreas mimicking adenocarcinomardquo BMJ CaseReports 2013

[10] S Gaur ldquoSarcoidosis manifested as hypercalcemic pancreatitisrdquoSouthern Medical Journal vol 94 no 9 pp 939ndash940 2001

[11] R Sanchez-Lozada J Soriano-Rosas and R Gutierrez-VegaldquoAcute pancreatitis diabetes and sarcoidosis case report andreview of the literaturerdquo Gaceta Medica de Mexico vol 140 no3 pp 343ndash346 2004

[12] M Gschwantler G Kogelbauer W Klose B Bibus DTscholakoff andWWeiss ldquoThepancreas as a site of granuloma-tous inflammation in Crohnrsquos diseaserdquo Gastroenterology vol108 no 4 pp 1246ndash1249 1995

[13] D S Strayer and J Kapp ldquoInsulin-specific antibodies andinsulitis in mice immunized with purified porcine insulinrdquoClinical and Experimental Immunology vol 47 no 1 pp 77ndash841982

[14] V DeshpandeMMino-KenudsonW Brugge and G Y Lauw-ers ldquoAutoimmune pancreatitis More than just a pancreaticdisease A contemporary review of its pathologyrdquo Archives ofPathology andLaboratoryMedicine vol 129 no 9 pp 1148ndash11542005

[15] R G Naik B M Brooks-Worrell and J P Palmer ldquoLatent auto-immune diabetes in adultsrdquo Journal of Clinical Endocrinologyand Metabolism vol 94 no 12 pp 4635ndash4644 2009

[16] R D G Leslie H Kolb N C Schloot et al ldquoDiabetes clas-sification grey zones sound and smoke action LADA 1rdquo Dia-betesMetabolism Research and Reviews vol 24 no 7 pp 511ndash519 2008

[17] J Wright A Yates H Sharma and P Thibert ldquoHistopatholog-ical lesions in the pancreas of the BBWistar rat as a function of

age and duration of diabetesrdquo Journal of Comparative Pathologyvol 95 no 1 pp 7ndash14 1985

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


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Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Table 1 Antibodies and their dilutions used in the study

Antibody Source Supplier Dilution

Anti-insulin Mouse monoclonal Diagnostic Biosystems 1 50clone E2E3

Anti-CD45R0 Mouse monoclonal DAKO Cytomation 1 200clone UCHL 1

Anti-CD20cy Mouse monoclonal DAKO Cytomation 1 100clone L26

Anti-alpha-1 Mouse monoclonal Acris Antibodies 1 400Antichymotrypsin clone ACT14C7

Anti-CD68 Mouse monoclonal DAKO Cytomation 1 100clone PG-M1

Antichromogranin A Rabbit polyclonal DAKO Cytomation 1 600

(a) (b)

Figure 1 Focal inflammatory infiltrates within the pancreatic parenchyma Haematoxylin and eosin times100 (a) Dispersed granulomas formedpredominantly of epithelioid cells Haematoxylin and eosin times40 (b)

stained with haematoxylin and eosin and by immunohis-tochemical methods using N-Histofine Immunohistochem-ical staining reagent (Nichirei Biosciences Japan) and 3-31015840diaminobenzidine as a chromogen to visualize the reactionThe list of antibodies including manufacturers and thedilutions used is introduced in Table 1

4 Results

Microscopic examination of pancreatic tissue discovered anincreased amount of lipomatous tissue within the pancre-atic lobules Irregular inflammatory infiltrates of a vari-able density composed predominantly of small lymphocytesand sparse neutrophilic and eosinophilic granulocytes werealso observed (Figure 1(a)) Multiple dispersed small (upto 500120583m) noncaseating epithelioid granulomas with giantcells without Schaumann bodies were present within thepancreatic lobules (Figures 1(b) and 2) Pancreatic islets werenot found Other organs examined histologically that islungs kidneys and liver did not display any granulomatouschanges

Immunohistological examination showed strong immu-noreactivity of macrophages forming the granulomas for

CD68 (Figure 2) and 120572-1 antichymotrypsin Inflammatoryinfiltrates were composed predominantly of CD45R0 positivesmall T-lymphocytes and scattered CD20 positive small Bcells Immunohistological detection of markers of neuroen-docrine differentiation (chromogranin A synaptophysin)and pancreatic hormones (insulin glucagon) verified theoriginal microscopic finding of absence of islets of Langer-hans (Figure 3)

5 Discussion

Granulomatous pancreatitis is a rare condition infrequentlydescribed in infectious diseases like tuberculosis or syphilisand in systemic inflammations Pancreatic tuberculosis isclinically nonspecific Radiological findings can resemble theneoplastic process or chronic inflammation Morphologi-cally it is characterized by caseating granulomas caseousnecrosis can be observed even in fine needle aspirationcytology [4 5] Syphilitic pancreatitis is an acquired diseaseextremely rare It is manifested in the tertiary syphilisClinically jaundice vague epigastric discomfort diarrhoeaand fatigue can appear In the microscopic examination













Acknowledgments



References
























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




























Acknowledgments



References
























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















References
























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















case report granulomatous pancreatitis in a patient with...

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