Adrenocorticotropic hormone-secreting pancreatic neuroendocrine carcinoma with m

lNTRODUCTlON

Neuroendocrine tumors or neuroendocrine neoplasms are classified by the World Health Organization into "well-differentiated" and "poorly differentiated" neuroendocrine carcinomas[1].Ectopic adrenocorticotropic hormone(ACTH)-secreting neuroendocrine tumors account for 9%-18% of Cushing's syndrome cases[2].Among ectopic ACTH-secreting tumors,pancreatic neuroendocrine(pNE)tumors are rare(4%-16%)but very aggressive tumors[3].Previous studies have shown that patients with ACTH-secreting pNE neoplasms have a poorer prognosis than patients with insulinoma,gastrinoma,and non-functioning pNE tumors[4].In addition,pneumocystis pneumonia,pulmonary embolism,and other complications have been reported as causes of death in patients with ACTH-secreting pNE tumors[5-8].However,previous reports provided no detailed clinical descriptions of the morbid complications of ACTH-secreting pNE tumors.Clinical follow-up with studies using radioisotope scans is also lacking.Here we report the detailed clinical course of a rapidly progressive case of ACTH-secreting pNE tumor that developed several complications,including multiple organ infections due to many types of pathogens,disseminated intravascular coagulation,and pulmonary thromboembolism.This case study shows that the progressive and aggressive nature of ACTH-secreting pNE tumors gives no truce for treating the disease with more effective therapeutic modalities,including surgical resection.

CASE PRESENTATlON

Chief complaints

The chief complaints of the patient were systemic edema and epigastric discomfort.

History of present illness

Two months before admission to our institution,a 78-year-old Japanese woman consulted a medical center due to systemic edema and epigastric discomfort.Laboratory analysis showed no abnormalities.Therefore,close clinical follow-up was suggested.However,blood analysis performed two months later revealed a high hemoglobin A1c(5.5%-7.2%)and decreased potassium concentration(2.7 mEq/L).Screening of potential causes of secondary diabetes mellitus showed high levels of cortisol(80.6 μg/dL)and ACTH(177 pg/mL)in the early morning and increased levels of cortisol(56.2 μg/dL)at midnight.The daily urine cortisol level(6550 μg/day)was also increased.A dexamethasone suppressive test(8 mg)showed no suppression of fasting blood cortisol(118 μg/dL)or ACTH(342 pg/mL).These results suggested the diagnosis of ACTH-dependent hypercortisolism(Table 1).An abdominal computed tomography(CT)scan showed a 3-cm tumor with poor contrast in the pancreatic tail(Figure 1).Cytological findings of endoscopic ultrasound-guided fine-needle aspiration showed cell clusters forming no specific structures with a high nuclear/cytoplasmic ratio,suggesting adenocarcinoma(Figure 2A).However,the immunostaining results showed positivity for chromogranin A,synaptophysin,CD 56,and ACTH(Figure 2B-E)that were compatible with the diagnosis of ACTH-secreting pNE neoplasm.The Ki-67 index was approximately 40%(Figure 2F).The patient was then referred to Mie University Hospital for subsequent examinations and treatment.

For some months the king’s grief was great; then gradually he began to forget a little, and, besides, his counsellors were always urging him to seek another wife. At first he refused to listen to them, but by-and-by he allowed himself to be persuaded to think of it, only stipulating7 that the bride should be more beautiful and attractive than the late queen, according to the promise he had made her.

History of past illness

There was no remarkable past or family history.She had no history of allergy,excessive alcohol consumption,or smoking.

Physical examination

The authors have read the CARE Checklist(2016),and the manuscript was prepared and revised according to the CARE Checklist(2016).

The Prince s next idea for Potentilla s amusement was to cause a fleet of boats exactly like those of Cleopatra, of which you have doubtless read in history, to come up the little river, and upon the most gorgeously decorated of these reclined the great Queen herself, who, as soon as she reached the place where Potentilla sat in rapt attention, stepped majestically37 on shore and presented the Princess with that celebrated38 pearl of which you have heard so much, saying: You are more beautiful than I ever was

Laboratory examinations

Laboratory analysis revealed thrombocytopenia with elevated blood levels of D-dimer,fibrinogen/fibrin degradation products,liver enzymes,cortisol and ACTH,and hypokalemia(Table 1).Brain magnetic resonance imaging(MRI)showed no pituitary tumor.Blood culture was negative,but urine culture was positive for

and

.Esophageal candidiasis was diagnosed by esophagogastroduodenoscopy.The patient was also positive for Cytomegalovirus antigen(C7-HRP,on day 1,132/82500 cells)associated with increased levels of liver enzymes(AST 121 U/L,ALT 294 U/L on day 1),and thus Cytomegalovirus hepatitis was diagnosed.Additional laboratory analysis on day 7 revealed an increased level of β-D glucan(48.0 pg/mL),and a chest CT scan on day 9 showed bilateral ground-glass opacity(Figure 3A and B)suspicious for Pneumocystis pneumonia.

Imaging examinations

Somatostatin receptor scintigraphy with

In-pentetoreotide performed on day 21 showed no uptake in any organ(Figure 4A).However,an

F-fluorodeoxyglucose-positron emission tomography(PET)performed on day 29 showed positive uptake in the pancreatic tumor and the liver(S6 segment;Figure 4B and C).Enhanced CT imaging taken before transfer to Mie University Hospital showed notumor in the liver S6 segment(Figure 4D).Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid(Gd-EOB-DTPA)-MRI revealed multiple liver tumors suggesting liver metastases(Figure 4E and F).Based on these findings,surgical intervention was canceled.

MULTlDlSClPLlNARY EXPERT CONSULTATlON

In addition to laboratory findings of disseminated intravascular coagulation,venous ultrasonography of the lower extremities performed on day 1 revealed deep venous thrombosis in the right popliteal segment of the femoral vein(size not recorded),right soleus vein(5-6 cm),and left posterior tibial vein(4 cm).In addition,pulmonary embolism was pointed out by a radiologist based on a chest CT scan taken on day 9(Figure 3D and E).

The moment the rabbit felt the flames he cried out Itchi, Itchi, I am burning; pull me out quick, my friend! But the little hare only laughed, and said, No, you may stay there! It is your own fault

FlNAL DlAGNOSlS

The word alone Gerda understood very well, and knew how much it expressed. So then she told the crow the whole story of her life and adventures, and asked him if he had seen little Kay.

TREATMENT

22.She had excellent notions:Cinderella is an intelligent and artistic70 woman. She knows how to make clothing appear at its best which was an important skill in her time. She only has rags to wear herself, but she has the taste to work with the finest materials. This was a sign of femininity.

The urinary tract infection was treated with meropenem(2 g/day,days 2 to 5)and ceftazidime(2 g/day,days 6 to 15).Esophageal candidiasis was treated with oral fluconazole(100 mg/day,from days 1 to 15).Cytomegalovirus hepatitis was empirically treated with foscarnet(5 g/day)from day 5 after admission.Treatment with foscarnet was stopped on day 27 because the liver enzymes improved(AST 32 U/L,ALT 66 U/L on day 9),and the C7-HRP test was negative.

The pulmonary infiltrates(Figure 3A and B)suspicious for Pneumocystis pneumoniae were treated with oral trimethoprim-sulfamethoxazole(480-2400 mg/day)for 3 wk.The β-D glucan level(10.4 pg/mL)decreased,and the respiratory status was stable on day 27.Prednisolone(25 mg/day)was added to the treatment because another radiological study disclosed organizing pneumonia on day 29 (Figure 3C).Treatment with oral trimethoprim-sulfamethoxazole(80-400 mg/day,three times a week)was also continued.

The patient's hypercoagulable states and thrombotic complications were treated with nafamostat mesylate(200 mg/day,days 1 to 9)and gabexate mesylate(1500 mg/day,days 10 to19).Due to the presence of severe thrombocytopenia,the patient received 10 units of platelet transfusion on day 6.A radiologist pointed out pulmonary embolism based on a chest CT scan taken on day 9(Figure 3D and E).Treatment with apixaban was started from day 11(20 mg/day for the first 7 days,10 mg/day thereafter).Disseminated intravascular coagulation improved,and the thrombi in the pulmonary artery and deep veins completely disappeared on day 88.

OUTCOME AND FOLLOW-UP

The multiple organ infections and thromboses responded well to antimicrobial and anticoagulant therapy.However,a radioisotope study with PET disclosed a pancreatic tumor and a metastatic lesion in the liver,whereas somatostatin receptor scintigraphy showed negative findings,suggesting that the primary and metastatic tumors were poorly differentiated and rapidly progressive.Based on these findings,surgical intervention was canceled.The patient was then transferred to another institution for antitumor chemotherapy.However,she died four months later due to rapid tumor progression.

DlSCUSSlON

ACTH-secreting pNE tumors are rare malignant diseases with aggressive behavior[3].Patients with this malignant disease have a poorer prognosis than patients with insulinoma,gastrinoma,or nonfunctioning ACTH-secreting pNE tumors[4].However,the explanation for the tumor aggressiveness and the poor patient prognosis remains unclear.A previous study suggested that hypomethylation of the proopiomelanocortin promoter may potentiate the ACTH secretory property of the tumors[8].A high Ki-67 index indicates poor clinical outcomes in pNE tumors[1,9].The Ki-67 index was high in our present case.A pathological diagnosis of a poorly differentiated pNE tumor also predicts a poor prognosis[1].Cytological study of samples taken by needle aspiration was available in our patient.However,it was difficult to determine the tumor differentiation status based only on the cytological material.Previous reports suggested that radioisotope techniques may help determine cell differentiation status.

In addition to allowing localization of the primary malignant tumor and metastatic lesion,radioisotope studies of pNE tumors may provide information on the tumor cell metabolic activity and the expression of specific receptors such as somatostatin receptors[10].In the current case,we performed somatostatin receptor scintigraphy using

In-pentetoreotide and PET using

F-fluorodeoxyglucose.The PET study confirmed the primary pNE tumor and the presence of liver metastasis,whereas the scintigraphy disclosed no tumor uptake.The combination of positive

F-fluorodeoxyglucose uptake by PET and negative

In-pentetoreotide uptake by scintigraphy indicates poor differentiation of pNE tumor cells[11,12].Malcolm

[10]reported a sensitivity of 57% for somatostatin receptor scintigraphy using

In-pentetoreotide and 100% for

F-fluorodeoxyglucose-PET in Grade 3 pNE tumors.Another study showed that metastasis of highly differentiated pNE tumors can be detected by somatostatin receptor scintigraphy using

In-pentetoreotide but not by

F-fluorodeoxyglucose-PET[13].In the present case,the

F-fluorodeoxyglucose-PET study showed positive radioisotope uptake in the primary pNE tumor and metastatic liver lesion,but the scintigraphy showed no radioisotope uptake,suggesting that the primary and metastatic pNE tumor was not differentiated.

In the current case,the ACTH-secreting pNE tumor was associated with multiple organ infections,including urinary tract infection,viral hepatitis,esophageal candidiasis,and bilateral pulmonary infiltrates suspicious for

pneumonia.Patients with hypercortisolemia are immunocompromised[14].Immunosuppression in patients with hypercortisolism is generally characterized by the reduced bactericidal function of neutrophils,decreased CD14- and CD16-mediated phagocytic activity of monocytes,deficient cytotoxic activity of natural killer cells,and reduced number of CD4+T cells[14].The current case showed a reduction in lymphocytes,including CD4+cells,and decreased peripheral blood concentration of IgG,suggesting she was an immunocompromised host.However,infections with multiple microbes responded well to antibacterial,antifungal,and antiviral drugs.The diagnosis of

pneumonia in our patient was not confirmed by microscopic observation of

or positivity by polymerase chain reaction.However,we initiated therapy for

pneumonia after suspecting the disease based on lung CT findings as delayed treatment of

pneumonia may be fatal in patients with ectopic ACTH syndrome[5,15,16].

Yoshihara A and Nishihama K were responsible for clinical treatment,follow-up of the patient,and manuscript preparation;Inoue C,Okano Y,Eguchi K,Tanaka S,and Maki K were responsible for clinical treatment,follow-up of the patient,and data interpretation;Fridman D'Alessandro V contributed to data interpretation;Takeshita A,Yasuma T,and Uemura M were responsible for radiological and pathological investigation;Yasuma T,Suzuki T,Gabazza EC,and Yano Y were responsible for data interpretation,intellectual contribution,and manuscript preparation.

CONCLUSlON

This report described the clinical course of a rapidly progressive case of ACTH-secreting pNE tumor who developed infectious complications due to many types of pathogens in multiple organs,widespread thromboses,pulmonary embolism,and disseminated intravascular coagulation.This case study shows that neuroendocrine carcinoma of the pancreas secreting ACTH has a poor immune state and that the progressive and aggressive nature of ACTH-secreting pNE tumors gives no truce for treating the disease with more effective therapeutic modalities,including surgical resection.

ACKNOWLEDGEMENTS

The authors would like to thank Dr.Tetsuya Murata from the JA Suzuka General Hospital Division of Pathology.

FOOTNOTES

In the current case,the ACTH-secreting pNE tumor was also associated with many thrombotic complications,including thrombus formation in many limb peripheral veins,pulmonary embolism,and disseminated intravascular coagulation.Patients with hypercortisolemia are in a hypercoagulable state[17].Hypercortisolism may cause hypercoagulability,although the precise mechanism is unclear.Alterations in the blood levels of von Willebrand factor and factor VIII have been reported[17].Some polymorphisms appear to affect the promoter activity of the von Willebrand factor gene in response to glucocorticoids,and a high concentration of cortisol may alter the multimeric structure of von Willebrand factor[17].Decreased physical activity during hospitalization or the perioperative period is also a contributing factor to increased risk of venous thrombosis and pulmonary embolism in patients with hypercortisolemia[18,19].The risk of thrombosis was high in our patient because of reduced physical activity and the presence of malignancy and infectious diseases[20,21].Our patient had a decreased number of platelets on admission.We delayed the treatment with anticoagulant therapy to prevent fatal hemorrhage.However,earlier anticoagulation therapy would have improved the thrombotic complications in the patient.

Written informed consent was obtained from the patient to publish clinical details and images when she was alive.

The pancreas tumor-related hypercortisolism and hypokalemia were treated with metyrapone(1500 to 3000 mg/day),hydrocortisone(60 mg/day),potassium chloride(2400-3600 mg/day)and spironolactone(50 mg/day).Hyperglycemia was treated with multiple daily insulin injections(up to 25 U/day,days 1 to 48)and oral repaglinide(0.75 mg/day).The response to therapy was good with a postprandial blood glucose level of 172 mg/dL,and HbA1c of 5.5% on day 88.

Yutaka Yano reports receiving lecture fees from Novo Nordisk.Other authors declared no conflict of interest concerning this case report.

The patient's final diagnosis was ACTH-secreting pNE tumor with ACTH-dependent hypercortisolism associated with urinary tract infection,Cytomegalovirus hepatitis,esophageal candidiasis,pulmonary infiltrates suspicious for

pneumonia,and widespread peripheral deep vein thromboses,pulmonary embolism,and disseminated intravascular coagulation.

The clinical findings on admission to Mie University Hospital were as follows: height 157.5 cm,body weight 54 kg,blood pressure 135/79 mmHg,and pulse rate 91 bpm.In addition,the patient presented a "moon-face" with bilateral pitting edema on the lower limbs on physical examination.

This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers.It is distributed in accordance with the Creative Commons Attribution NonCommercial(CC BYNC 4.0)license,which permits others to distribute,remix,adapt,build upon this work non-commercially,and license their derivative works on different terms,provided the original work is properly cited and the use is noncommercial.See: https://creativecommons.org/Licenses/by-nc/4.0/

32. Velvet and silk: To dream of wearing silk clothes is a sign of high ambition being gratified and friendly relations will be established between those who were estranged77 (Miller 512). Velvet portends78 a successful enterprise . . . it denotes that she will have honors bestowed79 upon her (Miller 577).Return to place in story.

Japan

Akihiro Yoshihara 0000-0001-5799-2440;Kota Nishihama 0000-0002-0471-5164;Chisa Inoue 0000-0002-7022-9156;Yuko Okano 0000-0002-8441-423X;Kazuhito Eguchi 0000-0002-4968-0217;Soichiro Tanaka 0000-0002-8240-6180;Kanako Maki 0000-0001-7061-0291;Valeria Fridman D'Alessandro 0000-0002-3719-1686;Atsuro Takeshita 0000-0002-3792-7382;Taro Yasuma 0000-0002-9117-5679;Mei Uemura 0000-0002-9140-0311;Toshinari Suzuki 0000-0003-0980-1763;Esteban C Gabazza 0000-0003-2536-898X;Yutaka Yano 0000-0003-0234-1207.

Ma YJ

So Tsarevitch Ivan mounted the Gray Wolf and the Tsarevna rode on the Horse with the Golden Mane, and at length they came to the forest where the Wolf had devoured Tsarevitch Ivan s horse.

Webster JR

Well, there are five signed in. So I went straight out and called the first name. Five bodies showed up at my triage desk, a pale petite woman and four small children in somewhat rumpled4 clothing.

Ma YJ

1 Nagtegaal ID,Odze RD,Klimstra D,Paradis V,Rugge M,Schirmacher P,Washington KM,Carneiro F,Cree IA;WHO Classification of Tumours Editorial Board.The 2019 WHO classification of tumours of the digestive system.

2020;76: 182-188[PMID: 31433515 DOI: 10.1111/his.13975]

2 Wajchenberg BL,Mendonca BB,Liberman B,Pereira MA,Carneiro PC,Wakamatsu A,Kirschner MA.Ectopic adrenocorticotropic hormone syndrome.

1994;15: 752-787[PMID: 7705280 DOI: 10.1210/edrv-15-6-752]

3 Falconi M,Eriksson B,Kaltsas G,Bartsch DK,Capdevila J,Caplin M,Kos-Kudla B,Kwekkeboom D,Rindi G,Klöppel G,Reed N,Kianmanesh R,Jensen RT;Vienna Consensus Conference participants.ENETS Consensus Guidelines Update for the Management of Patients with Functional Pancreatic Neuroendocrine Tumors and Non-Functional Pancreatic Neuroendocrine Tumors.

2016;103: 153-171[PMID: 26742109 DOI: 10.1159/000443171]

4 Maragliano R,Vanoli A,Albarello L,Milione M,Basturk O,Klimstra DS,Wachtel A,Uccella S,Vicari E,Milesi M,Davì MV,Scarpa A,Sessa F,Capella C,La Rosa S.ACTH-secreting pancreatic neoplasms associated with Cushing syndrome: clinicopathologic study of 11 cases and review of the literature.

2015;39: 374-382[PMID: 25353285 DOI: 10.1097/PAS.0000000000000340]

5 Cristante J,Lepelley M,Mallaret M,Carreau A,Chabre O.Pneumocystis pneumonia can complicate medical treatment of hypercortisolism even in outpatients with Cushing's disease.

2020;81: 551-560[PMID: 33278378 DOI: 10.1016/j.ando.2020.11.002]

6 Schernthaner-Reiter MH,Siess C,Micko A,Zauner C,Wolfsberger S,Scheuba C,Riss P,Knosp E,Kautzky-Willer A,Luger A,Vila G.Acute and Life-threatening Complications in Cushing Syndrome: Prevalence,Predictors,and Mortality.

2021;106: e2035-e2046[PMID: 33517433 DOI: 10.1210/clinem/dgab058]

7 Shayesteh S,Fouladi DF,Fishman EK,Kawamoto S.Ectopic Cushing syndrome caused by a pancreatic neuroendocrine tumor: A case report.

2020;15: 1014-1017[PMID: 32547669 DOI: 10.1016/j.radcr.2020.04.009]

8 Zhang C,Jin J,Xie J,Ye L,Su T,Jiang L,Zhou W,Jiang Y,Wu L,Wang T,Zhong X,Ning G,Shen B,Wang W.The Clinical Features and Molecular Mechanisms of ACTH-secreting Pancreatic Neuroendocrine Tumors.

2020;105[PMID: 32785672 DOI: 10.1210/clinem/dgaa507]

9 Hamilton NA,Liu TC,Cavatiao A,Mawad K,Chen L,Strasberg SS,Linehan DC,Cao D,Hawkins WG.Ki-67 predicts disease recurrence and poor prognosis in pancreatic neuroendocrine neoplasms.

2012;152: 107-113[PMID: 22503317 DOI: 10.1016/j.surg.2012.02.011]

10 Squires MH 3rd,Volkan Adsay N,Schuster DM,Russell MC,Cardona K,Delman KA,Winer JH,Altinel D,Sarmiento JM,El-Rayes B,Hawk N,Staley CA 3rd,Maithel SK,Kooby DA.Octreoscan Versus FDG-PET for Neuroendocrine Tumor Staging: A Biological Approach.

2015;22: 2295-2301[PMID: 25786743 DOI: 10.1245/s10434-015-4471-x]

11 Chan DL,Pavlakis N,Schembri GP,Bernard EJ,Hsiao E,Hayes A,Barnes T,Diakos C,Khasraw M,Samra J,Eslick E,Roach PJ,Engel A,Clarke SJ,Bailey DL.Dual Somatostatin Receptor/FDG PET/CT Imaging in Metastatic Neuroendocrine Tumours: Proposal for a Novel Grading Scheme with Prognostic Significance.

2017;7: 1149-1158[PMID: 28435454 DOI: 10.7150/thno.18068]

12 Kubota K,Okasaki M,Minamimoto R,Miyata Y,Morooka M,Nakajima K,Sato T.Lesion-based analysis of(18)F-FDG uptake and(111)In-Pentetreotide uptake by neuroendocrine tumors.

2014;28: 1004-1010[PMID: 25179521 DOI: 10.1007/s12149-014-0900-3]

13 Yasuda M,Takeda S,Lee M,Hoshi S,Hoshi T,Tanaka Y,Miyajima S,Takaya H,Kajimura K.Small Cystic Pancreatic Neuroendocrine Neoplasm with Huge Liver and Bone Metastases.

2020;59: 3027-3032[PMID: 33268697 DOI: 10.2169/internalmedicine.5038-20]

14 Hasenmajer V,Sbardella E,Sciarra F,Minnetti M,Isidori AM,Venneri MA.The Immune System in Cushing's Syndrome.

2020;31: 655-669[PMID: 32387195 DOI: 10.1016/j.tem.2020.04.004]

15 Colby C,McAfee S,Sackstein R,Finkelstein D,Fishman J,Spitzer T.A prospective randomized trial comparing the toxicity and safety of atovaquone with trimethoprim/sulfamethoxazole as Pneumocystis carinii pneumonia prophylaxis following autologous peripheral blood stem cell transplantation.

1999;24: 897-902[PMID: 10516703 DOI: 10.1038/sj.bmt.1702004]

16 Song Y,Ren Y,Wang X,Li R.Recent Advances in the Diagnosis of Pneumocystis Pneumonia.

2016;57: E111-E116[PMID: 27904052 DOI: 10.3314/mmj.16-00019]

17 Trementino L,Arnaldi G,Appolloni G,Daidone V,Scaroni C,Casonato A,Boscaro M.Coagulopathy in Cushing's syndrome.

2010;92 Suppl 1: 55-59[PMID: 20829619 DOI: 10.1159/000314349]

18 Suarez MG,Stack M,Hinojosa-Amaya JM,Mitchell MD,Varlamov EV,Yedinak CG,Cetas JS,Sheppard B,Fleseriu M.Hypercoagulability in Cushing Syndrome,Prevalence of Thrombotic Events: A Large,Single-Center,Retrospective Study.

2020;4: bvz033[PMID: 32064411 DOI: 10.1210/jendso/bvz033]

19 Wagner J,Langlois F,Lim DST,McCartney S,Fleseriu M.Hypercoagulability and Risk of Venous Thromboembolic Events in Endogenous Cushing's Syndrome: A Systematic Meta-Analysis.

2018;9: 805[PMID: 30745894 DOI: 10.3389/fendo.2018.00805]

20 Abdol Razak NB,Jones G,Bhandari M,Berndt MC,Metharom P.Cancer-Associated Thrombosis: An Overview of Mechanisms,Risk Factors,and Treatment.

2018;10[PMID: 30314362 DOI: 10.3390/cancers10100380]

21 Mullard A,Innes H.Venous thromboembolism in malignancy.

2014;14: 532-534[PMID: 25301917 DOI: 10.7861/clinmedicine.14-5-532]