AERTS, JG

ELTE, JW

MANINTVELD, OC

NOORLANDER, I

Praet, Marleen

Tournoy, Kurt

Van Meerbeeck, Jan

English

Noorlander, I.

Elte, J. W.

Manintveld, O. C.

Aerts, J. G.

Ghent University Academic Bibliography

Lung Cancer (2006) 51, 251—255CASE REPORTA case of recurrent non-small-cell lung carcinomaand paraneoplastic Cushing’s syndromeI. Noorlandera, J.W. Elteb, O.C. Manintveldb, K.G. Tournoyc,M.M. Praetd, J.P. van Meerbeeckc, J.G. Aertsa,∗a Sint Franciscus Gasthuis, Department of Respiratory Diseases, Kleiweg 500, 3045 PM Rotterdam,The Netherlandsb Sint Franciscus Gasthuis, Department of Internal Medicine, Rotterdam, The Netherlandsc Ghent University Hospital, Thoracic Oncology Unit, Ghent, Belgiumd Ghent University Hospital, Department of Pathology, Ghent, BelgiumReceived 4 July 2005; received in revised form 24 August 2005; accepted 24 August 2005KEYWORDSCushing;Ectopic ACTH;Non-small-cell lungcarcinomaSummary Secretion of ectopic adrenocorticotropic hormone (ACTH) with con-sequently Cushing’s syndrome is a rare paraneoplastic phenomenon. It has beendescribed in a variety of malignancies, like bronchial carcinoids, small-cell lungcarcinoma, thymoma, pancreatic carcinoma and other. In many cases of suspectedectopic ACTH secretion, it is difﬁcult to histologically or cytochemically conﬁrm thediagnosis. We present a 63-year-old woman with a recurrent poorly differentiatedsquamous cell lung carcinoma with clinical and biochemical features consistent withectopic Cushing’s syndrome. Immunocytochemical staining conﬁrmed the secretionof ACTH by tumour cells.© 2005 Elsevier Ireland Ltd. All rights reserved.1. Introduction‘‘The name of Harvey Cushing (1869—1939) wasimmortalized in the history of medicine, by his dis-covery, in 1912, of Cushing’s disease, an endocrinesyndrome caused by a malfunction of the pituitarygland. This discovery was described in detail in: ThePituitary Body and its Disorders [1].’’∗ Corresponding author. Tel.: +31 10 4616149;fax: +31 10 4612692.E-mail address: j.aerts@sfg.nl (J.G. Aerts).Cushing’s syndrome is characterized by truncalobesity, a ‘buffalo hump’ and/or ‘moon face’, pur-plish abdominal striae, ecchymoses and proximalmyopathy, accompanied by non-speciﬁc symptomslike edema, hypertension, fatigability and weak-ness, hirsutism, hyperpigmentation and diabetes.The syndrome can be ACTH-independent due toautonomous glucocorticoid-secreting adrenocorti-cal adenomas or carcinomas. However, in mostcases Cushing’s syndrome is ACTH-dependent. Theaetiology is bilateral adrenal hyperplasia due tohypersecretion of pituitary ACTH or ectopic produc-tion of ACTH by a non-pituitary cause like malig-nancy, respectively called Cushing’s disease and0169-5002/$ — see front matter © 2005 Elsevier Ireland Ltd. All rights reserved.doi:10.1016/j.lungcan.2005.08.015252 I. Noorlander et al.Cushing’s syndrome. Numerous tumours have beenreported to secrete ACTH, like bronchial carci-noids, thymoma, pancreatic malignancy and small-cell lung carcinomas (SCLC).We present a patient with a previous history ofnon-small-cell lung carcinoma (NSCLC), typical fea-tures consistent with Cushing’s syndrome and medi-astinal lymphadenopathy on computerized tomog-raphy (CT).2. Case reportIn March 2005, a 63-year-old woman presented inour hospital with progressive dyspnea. She had ahistory of previous poorly differentiated squamouscell lung carcinoma of the lower right lobe in June2001. For this, she had a lobectomy in another hos-pital with pathological tumour-staging pT1N0M0.After the operation she had gradually gained 50 kgof weight, which she ascribed to cessation of smok-ing. In January 2005, the general practitioner diag-nosed her with hypertension and diabetes.At presentation, physical ﬁndings showed aplasma ACTH-level (223 ng/l, Ref. range 7—50)and plasma renin activity level (6.70 ng/ml/h, Ref.range 0.8—5.5). Serum cortisol failed to suppressfollowing 1mg dexamethasone overnight (09:00 hcortisol 1.55mol/l, Ref. range <0.14). Magneticresonance imaging (MRI) did not reveal adenomasof the pituitary gland, suggesting that our patienthad ectopic ACTH syndrome (EAS).To identify the source of the ectopic ACTH-production while considering her previous his-tory of a lung carcinoma, a thoracic CT-scan wasmade, which showed mediastinal lymphadenopa-thy. On the abdominal CT-scan, there were nosigns of adrenal hyperplasia or adenoma. Subse-quently bronchoscopy was performed which didnot reveal abnormalities. Curved linear endoscopicultrasound-guided ﬁne-needle aspiration (EUS-FNA)was performed to biopsy the enlarged lymph nodesand cytological examination demonstrated poorlydifferentiated squamous cell carcinoma. Assumingthe prior resected tumour in the lower right lobeto be the primary tumour, this lymph node can beregarded as N3. Immuno-cytochemical staining ofthis specimen was positive for the neuroendocrinemarker CD56 and for ACTH, suggesting paraneoplas-t(lnltof2swscto3IcIbacnwstCushingoid appearance, with a moon face, buffalohump and centripetal obesity. There were no signsof hirsutism or hyperpigmentation, nor where thereabdominal striae or ecchymoses. There was pit-ting edema of the legs and some tachypnea. Bloodpressure was elevated (RR 175/75mmHg). Her med-ication included a potassium sparing diuretic com-bined with a loop diuretic to control hypertensionand edema, a biguanide to control glucose-levelsand inhalation-corticosteroids.Initial laboratory evaluation revealed a severehypokalemia (K+ 1.8mmol/l, Ref. range 3.5—5.0)with normal sodium, magnesium and calcium-levelsand a normal renal function. Arterial blood gasanalysis revealed a metabolic alkalosis with hypox-emia (pH 7.60; BE 17.1; HCO3− 41.1mmol/l (Ref.range 22—29), pO2 53.6mmHg (7.15 kPa) and pCO240.0mmHg (5.33 kPa)).She was treated with intravenous and oralpotassium chloride and supplemental oxygen. Thediuretics were temporarily discontinued, howevera potassium-sparing diuretic had to be re-startedbecause of increasing edema of the legs. Hyper-tension was treated by an angiotensin I-blocker,utilizing its potassium-sparing quality.Further investigations revealed high 09:00 hplasma cortisol (1.58mol/l, Ref. range 0.18—0.72)with loss of diurnal variation (midnight plasmacortisol 1.43mol/l, Ref. range <0.21). Urinaryfree cortisol was also elevated (12.16mol/24 h,Ref. range 0.03—0.28mol/24 h), and so were theic Cushing’s syndrome (Fig. 1).The patient was treated with ketoconazole400mg three times daily) and plasma cortisolevels decreased, as did the potassium-suppletioneeded. She developed bacteraemia with Staphy-ococcus Aureus-species, originating from a con-aminated intravenous catheter. After two weeksf antibiotic treatment, induction-chemotherapyor TxN3M0 NSCLC was administered (Vinorelbin5mg/m2 and Cisplatin 80mg/m2). Ten days later,he developed bilateral pulmonary embolisms forhich low molecular weight heparin (LMWH) wastarted. The patient deceased 18 days after onset ofhemotherapy. Post-mortem autopsy revealed mul-iple bilateral pulmonary embolisms as direct causef death.. Discussionn ACTH-dependent Cushing’s syndrome 20—25% ofases are caused by ectopic ACTH syndrome (EAS).t is well known that several lung tumours likeronchial carcinoids and small cell lung carcinomare associated with EAS in approximately 1—5% ofases [2,3]. In recent literature, bronchial carci-oids seem to be the predominant cause of EAS,hile the incidence of SCLC associated with EASeems to decrease [9]. A possible explanation forhis might be the declining incidence of SCLC, apartParaneoplastic Cushing’s syndrome 253Fig. 1 Microscopy. (A) Giemsa Stain (200×): EUS-FNAreveals numerous neoplastic cells with anaplastic nuclei.(B) Immunocytochemistry with CD56 (200×): decorationof the neoplastic cells with CD56. (C) Immunocytochem-istry with ACTH (1000×): some neoplastic cells expressACTH.from the fact that SCLC associated with Cushing’ssyndrome will be less reported due to the knownassociation.A non-small cell lung carcinoma causing ACTH-dependent Cushing’s syndrome has been seldomreported. In 1975, Imura et al. [4] reported threepatients with adenocarcinoma of the lung, threepatients with undifferentiated lungcarcinoma andone patient with a squamous cell carcinoma ofthe lung, which were all accompanied by ectopicACTH secretion. However, these patients had noclinical signs of Cushing’s syndrome. Since then,only four case-reports of NSCLC associated withEAS have been published [5—8]. In two of thesecases, the diagnosis EAS could not be conﬁrmed bytumour cell staining for ACTH or ACTH-precursors[7,8]. In the present case, however, the cytologi-cal material obtained stains for ACTH. Revision ofthe initial pathology specimens of 2001 showed noACTH-expression by tumour cells at that time. It isknown that tumour-relapses can show further de-differentiation while developing neuro-endocrinefeatures such as ACTH-secretion. For squamous cellcarcinoma this is seldom seen.All variables strongly support paraneoplasticttcftmocl2iowomUmpdppcamocAmrpype of Cushing’s syndrome in this patient ratherhan a pituitary one. The existence of a lung car-inoma with positive immunocytochemical stainingor ACTH is the most important observation. Fur-hermore, a severe hypokalemic alkalosis is com-on in EAS and is found in 71—100% of casesf ectopic ACTH secretion, but only in 10% ofases of pituitary ACTH syndrome [9]. Serum ACTH-evels were markedly elevated and levels above00mol/l, as in our patient, are rare in pitu-tary Cushing’s syndrome. To exclude other causesf Cushing’s syndrome, MRI of the pituitary glandas performed. Although no micro-adenoma wasbserved, it is reported that about 50% of pituitaryicro-adenomas cannot be detected by MRI [21].nfortunately, obduction of the brain was not per-itted by the relatives of the deceased. Inferioretrosal sinus ACTH sampling may be important inistinguishing between pituitary and ectopic ACTH-roduction [10]. In our case however, this sam-ling was not performed because delay in inhibitingortisol-production with ketoconazole would neg-tively inﬂuence the primary outcome. Further-ore, delay could be regarded unethical becausef the ﬁnding of ACTH-positive cells by cytochemi-al staining.The ultimate manner to control paraneoplasticCTH syndrome is dependent on successful treat-ent of the primary tumour. There are severaleports about the complications of chemotherapy inatients with ectopic ACTH-production. The com-254 I. Noorlander et al.plications reported are mostly related to severeinfections and gastrointestinal bleeding or ulcer-ation [10,11]. A small study of Dimopoulos et al.[12] reported nine out of 11 patients with SCLCand paraneoplastic Cushing’s syndrome to deceasewithin two weeks after onset of chemotherapy.Shepherd et al. [11] found that ectopic ACTH-production is associated with a low response tochemotherapy, short survival and a high rate ofcomplication.Ketoconazole is used in the treatment of Cush-ing’s syndrome, as it primarily inhibits CYP11B1(11--hydroxylase) but also CYP11A1 (desmolase,cholesterol side-chain cleavage enzyme) in theadrenals. 11--hydroxylase is the enzyme respon-sible for the hydroxylation of 11-deoxycortisolto cortisol while desmolase converts cholesterolto ı-5-pregnenolone [13—15]. Only a few reportsabout the usefulness of glucosteroid biosynthesisinhibitors in ectopic ACTH syndrome are published,and they report controversial results [16—20]. Inthe study of Winquist et al., the conclusions werethat ketoconazole did not prolong survival, but itdid provide a palliative hormonal response in twothird of patients. In our patient, after administra-of three cases and review of the literature. Postgrad Med J2001;77(909):464—7.[4] Imura H, Matsukura S, Yamamoto H, Hirata Y, Nakai Y.Studies on ectopic ACTH- producing tumors. II. Clinicaland biochemical features of 30 cases. Cancer 1975;35(5):1430—7.[5] Myers EA, Hardman JM, Worsham GF, Eil C. Adenocarcinomaof the lung causing ectopic adrenocorticotropic hormonesyndrome. Arch Intern Med 1982;142(7):1387—9.[6] Schott R, Chaouat A, Tavernier M, Kessler R, Weitzenblum E.Paraneoplastic hypercorticism associated with a bronchialadenocarcinoma. Rev Mal Respir 1999;16(3):395—7.[7] Boon ES, Leers MP, Tjwa MK. Ectopic Cushing’s syn-drome in a patient with squamous cell carcinoma of thelung due to CRF-like production. Monaldi Arch Chest Dis1994;49(1):19—21.[8] Yoh K, Kubota K, Nomura M, Niho S, Goto K, Ohmatsu H, etal. Cushing’s syndrome associated with adenocarcinoma ofthe lung. Intern Med 2003;42(9):831—3.[9] Wajchenberg BL, Mendonca BB, Liberman B, PereiraMA, Carneiro PC, Wakamatsu A, et al. Ectopicadrenocorticotropic hormone syndrome. Endocr Rev1994;15(6):752—87.[10] Terzolo M, Reimondo G, Ali A, Bovio S, Daffara F, Paccotti P,et al. Ectopic ACTH syndrome: molecular bases and clinicalheterogeneity. Ann Oncol 2001;12(Suppl 2):S83—7.[11] Shepherd FA, Laskey J, Evans WK, Goss PE, Johansen E,Khamsi F. Cushing’s syndrome associated with ectopic corti-cotropin production and small-cell lung cancer. J Clin Oncol1992;10(1):21—7.[[[[[[[[[[tion of high doses of ketoconazole (400mg threetimes daily), serum cortisol-levels and subsequentlyhypokalemia were ﬁnally controlled.The present patient died of recurrent bilateralpulmonary thrombo-embolisms despite treatmentwith LMWH. Both active malignancy and Cushing’ssyndrome are associated with a hypercoagulablestate because of an increase in plasma clotting fac-tors like Factor VIII and von Willebrand factor com-plex, and to an impairment of ﬁbrinolytic capacity[22,23]. This could explain why our patient sufferedrecurrent pulmonary embolisms despite adequateanticoagulant treatment.In conclusion, we believe this patient presentedwith a Cushing’s syndrome paraneoplastic to apoorly differentiated squamous cell carcinoma ofthe lung. Although uncommon, ectopic Cushing’ssyndrome can also be found in NSCLC, and is asso-ciated with a worse prognosis due to severe com-plications.References[1] Sabbatini RME. The history of psychosurgery. Brain Mind Mag1997.[2] Delisle L, Boyer MJ, Warr D, Killinger D, Payne D, YeohJL, et al. Ectopic corticotropin syndrome and small-cellcarcinoma of the lung. Clinical features, outcome and com-plications. Arch Intern Med 1993;153(6):746—52.[3] Amer KM, Ibrahim NB, Forrester-Wood CP, Saad RA, Scan-lon M. Lung carcinoid related Cushing’s syndrome: report12] Dimopoulos MA, Fernandez JF, Samaan NA, Holoye PY,Vassilopoulou-Sellin R. Paraneoplastic Cushing’s syndromeas an adverse prognostic factor in patients who die earlywith small cell lung cancer. Cancer 1992;69(1):66—71.13] Sonino N. The use of ketoconazole as an inhibitor of steroidproduction. N Engl J Med 1987;317(13):812—8.14] Loose DS, Kan PB, Hirst MA, Marcus RA, Feldman D.Ketoconazole blocks adrenal steroidogenesis by inhibit-ing cytochrome P450-dependent enzymes. J Clin Invest1983;71(5):1495—9.15] Stalla GK, Stalla J, Huber M, Loefﬂer JP, Hollt V, von WerderK, et al. Ketoconazole inhibits corticotropic cell function invitro. Endocrinology 1988;122(2):618—23.16] Winquist EW, Laskey J, Crump M, Khamsi F, Shepherd FA.Ketoconazole in the management of paraneoplastic Cush-ing’s syndrome secondary to ectopic adrenocorticotropinproduction. J Clin Oncol 1995;13(1):157—64.17] Farwell AP, Devlin JT, Stewart JA. Total suppression ofcortisol excretion by ketoconazole in the therapy of theectopic adrenocorticotropic hormone syndrome. Am J Med1988;84(6):1063—6.18] Shepherd FA, Hoffert B, Evans WK, Emery G, TrachtenbergJ, Ketoconazole. Use in the treatment of ectopic adreno-corticotropic hormone production and Cushing’s syndromein small-cell lung cancer. Arch Intern Med 1985;145(5):863—4.19] Kornely E, Schlaghecke R, Horster FA. Palliative therapy ofan ectopic Cushing’s syndrome due to a metastatic carci-noid tumor. Klin Wochenschr 1991;69(4):173—6.20] Tabarin A, Navarranne A, Guerin J, Corcuff JB, Parneix M,Roger P. Use of ketoconazole in the treatment of Cushing’sdisease and ectopic ACTH syndrome. Clin Endocrinol (Oxf)1991;34(1):63—9.21] Puig J, Wagner A, Caballero A, Rodriguez-Espinosa J, WebbSM. Cost-effectiveness and accuracy of the tests used inthe differential diagnosis of Cushing’s syndrome. Pituitary1999;1(2):125—32.Paraneoplastic Cushing’s syndrome 255[22] Boscaro M, Sonino N, Scarda A, Barzon L, Fallo F, Sar-tori MT, et al. Anticoagulant profylaxis markedly reducestrombo-embolic complications in Cushing’s syndrome. ClinEndocrinol Metab 2002;87(8):3662—6.[23] Gouin-Thibault I, Achkar A, Samama MM. The throm-bophilic state in cancer patients. Acta Haematol2001;106(1/2):33—42.

A case of recurrent non-small-cell lung carcinoma and paraneoplastic Cushing's syndrome

A case of recurrent non-small-cell lung carcinoma and paraneoplastic Cushing's syndrome

Abstract

Similar works

Full text

Available Versions

Ghent University Academic Bibliography

EUR Research Repository

EUR Research Repository