A 60-year-old man with a pre-existing stable sacrococcygeal teratoma developed acromegaly, ectopic Cushing's syndrome, and 5HIAA secretion. To our knowledge, this represents the first reported case of ACTH and serotonin secretion, and likely GHRH or GH cosecretion, from a sacrococcygeal teratoma in an adult

Babiker, Tarig

Berney, Daniel M

Brooke, Antonia

Drake, William M

Gurnell, Mark

Kyrodimou, Efstathia

Clinical Case Reports

English

Tarig Babiker

Efstathia Kyrodimou

Daniel M. Berney

Mark Gurnell

William M. Drake

Antonia Brooke

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Acromegaly and Cushing's syndrome caused by a neuroendocrine tumor arising within a sacrococcygeal teratoma

Apollo (Cambridge)

CASE REPORTAcromegaly and Cushing’s syndrome caused by aneuroendocrine tumor arising within a sacrococcygealteratomaTarig Babiker1 , Efstathia Kyrodimou1, Daniel M. Berney2, Mark Gurnell3, William M. Drake4 &Antonia Brooke11Departments of Endocrinology and Histopathology, Royal Devon and Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UK2Department of Histopathology, Barts Cancer Institute, Queen Mary, University of London, London, EC1A7BE, UK3Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, National Institute for Health Research CambridgeBiomedical Research Centre, Addenbrooke’s Hospital, University of Cambridge, Cambridge, CB2 0QQ, UK4Department of Endocrinology, St Bartholomew’s Hospital, London, EC1A7BE, UKCorrespondenceTarig Babiker, Department of Diabetes andEndocrinology, Royal Devon and Exeter NHSFoundation Trust, Barrack Road, Exeter, EX25DW, UK. Tel: +441392411611;E-mail: tarig.babiker@nhs.netFunding InformationNo sources of funding were declared for thisstudy.Received: 7 February 2017; Revised: 27 May2017; Accepted: 20 July 2017Clinical Case Reports 2017; 5(11): 1768–1771doi: 10.1002/ccr3.1148Key Clinical MessageA 60-year-old man with a pre-existing stable sacrococcygeal teratoma developedacromegaly, ectopic Cushing’s syndrome, and 5HIAA secretion. To our knowl-edge, this represents the first reported case of ACTH and serotonin secretion,and likely GHRH or GH cosecretion, from a sacrococcygeal teratoma in anadult.KeywordsAcromegaly, ACTH, Cushing’s, neuroendocrine, teratoma.Case DescriptionA 60-year-old man presented with clinical features of acro-megaly. He had a background of type 1 diabetes, diagnosedaged 28 years, hypertension and a C3–C6 laminoplastyaged 54 years for cervical stenosis. He had continuedsurveillance following an exploration and partial resectionof a sacral dermoid cyst aged 8 years. CT imaging showeda complex, partly cystic, partly solid presacral mass withsome erosion of the lower sacrum and coccyx (Fig. 1). Thecystic component had required intermittent radiological-guided drainage to relieve abdominal pain.Endocrine testing confirmed growth hormone (GH)excess (nadir serum GH after 75 g oral glucose 9.8 mcg/L;serum IGF-1 72.4 nmol/L (reference range 9.0–40.0)). Thepituitary gland was homogenous on T1-weighted magneticresonance imaging (MRI), with no focal mass lesion,although with a convex superior margin. Repeat pituitaryimaging with T1- and T2-weighted and T1 dynamicsequences showed no clear focal abnormality, but persistentconvexity of the superior aspect of the gland. Due to theabsence of a definite surgical target, he was initially treatedmedically. However, dopamine agonist and somatostatinanalogue therapy were poorly tolerated due to unpredictablehypoglycemic events and gastrointestinal side effects and,after a period of time, medical therapy was stopped.11C-methionine PET-CT coregistered with volumetricMRI demonstrated diffuse hyperintensity within the pitu-itary, but no discrete lesion. Somatostatin receptorscintigraphy was reported to show physiological uptakein the bladder and physiological uptake in the pituitarysella. He underwent pituitary exploration and partialtransphenoidal hypophysectomy; histology revealed nor-mal pituitary tissue only, but 3 months postoperativelyhis serum IGF-1 was just 11 nmol/L (age-related refer-ence range 5–26 nmol/L) and has remained normalthereafter. Anterior pituitary function was otherwise nor-mal postoperatively.1768 ª 2017 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution License, which permits use,distribution and reproduction in any medium, provided the original work is properly cited.In the weeks preceeding surgery, he developed periph-eral edema. Within weeks of surgery, he was admittedwith severe fluid retention and abdominal bloating. Hehad gained 15 kg in weight with persistent hypokalemiadespite the use of potassium-sparing diuretics (amiloride,spironolactone). There was no proteinuria, and serumalbumin was 30 g/L and he had normal cardiac functionas determined by MRI. A pulmonary embolus was identi-fied on CT pulmonary angiogram but deemed not largeenough to cause cardiac strain, and there was no associ-ated inferior vena cava obstruction to explain his edema.He suffered recurrent infections: bilateral pneumonia, cel-lulitis, influenza, and norovirus-associated gastroenteritis.Cortisol excess was suspected and confirmed on a low-dose dexamethasone suppression test (cortisol postdexam-ethasone 1070 nmol/L) and an elevated midnight cortisol(>1750 nmol/L). ACTH was elevated (188 ng/L; referencerange 0–40 ng/L); with all tests performed after resolutionof his acute illness. Postoperative cortisol ranged between800 and 1728 nmol/L.Ectopic ACTH production from the presacral mass wasconsidered, and a core biopsy of this lesion revealed a well-differentiated neuroendocrine tumor with no mitoses seenand a Ki-67 of 1% (WHO grade G1 [1]). Immunochemistrydemonstrated CAM5.2-positive cytokeratin immunoreac-tivity and cytoplasmic staining for synaptophysin andACTH (Fig. 1). Immunostaining for other(A)(B)Figure 2. (A and B) T1-weighted axial magnetic resonance image (A)and T1-weighted turbo inversion recovery magnitude (TIRM) coronalmagnetic resonance image. These demonstrate the large mixed fluidcontaining (red arrows) and heterogeneous soft tissue (yellow) areasof the presacral pelvic mass consistent with a teratodermoidintimately connected to, and possibly involving the sacrum, with softtissue extension posterior to the posterior sacral contour.(A)(B)(C)Figure 1. Histology of the trucut biopsy. (A) H&E showing a core ofwell-differentiated neuroendocrine tumor with bland ovoid nucleiarranged in a partially cribriforming and partly solid architecture. (B)Immunochemistry showing strong positivity for ACTH in the vastmajority of cells. (C) Immunochemistry for CAM 5.2 showing aperinuclear dot positivity, typical for neuroendocrine tumors.ª 2017 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd. 1769T. Babiker et al. Pluripotent endocrinopathy in a teratomaadenohypophysial hormones (including growth hormone)was negative; however, there was only a small amount of tis-sue. i(12)p was also negative, in keeping with teratomas aris-ing in this region, and distinguishing this maturesacrococcygeal teratoma from testicular-type mature ter-atomas which in adult males have malignant potential [2].Unfortunately, there was insufficient tissue for immunohisto-chemistry for GHRH. Serum alpha-fetoprotein and beta-HCG were normal and he had a normal testicular examina-tion (Fig. 2).Cushing’s syndrome was treated with a combination ofsubcutaneous octreotide (to reduce ACTH secretion),metyrapone, ketoconazole and, subsequently when eucor-tisolemia could not be achieved, intravenous etomidate2.5 mg/h. Once stabilized, he underwent bilateraladrenalectomy with resultant normalization of serumpotassium and marked improvement of his edema.Despite adrenalectomy and good recovery, he continuedto experience episodes of hypoglycemia, breathlessness,and anxiety with labile blood pressure. 5-hydroxyindolea-cetic acid (5HIAA) (153 lmol/24 h; reference range 4.7–36.2 lmol/24 h) and chromogranin B (1416 pmol/L; refer-ence range 0–150) were both elevated; chromogranin Awas normal. Although the raised 5HIAA was likely responsiblefor some of these symptoms, they did not completely resolvewith low-dose somatostatin analogue treatment, despiteimprovement of 5HIAA to 65.3 lmol/24 h, raising the possi-bility of additional hormonal cosecretion. The most recentACTH was 47 ng/L (posthydrocortisone), and IGF-1 hasremained normal both prior to, and after, recommencingsomatostatin analogue.DiscussionSacrococcygeal teratomas usually show fully differentiatedtissue derived from the ectoderm, endoderm, and meso-derm. A very small minority have malignant germ cell ele-ments and may secrete alpha-fetoprotein or beta-HCG [3].Most present in utero or in infancy with rectal or bladderobstruction, or rarely weakness, pain, or paralysis [4]. Arecent study suggests that sacrococcygeal teratomas can bedivided into two distinct histological groups, with the pres-ence of i(12)p associated with the presence of germ celltumor components [5]. Treatment is usually surgical withcomplete resection or, if the teratoma is part of a mixed-germ cell tumor, adjuvant platinum-based chemotherapymay be considered.In this case, core biopsy and immunohistochemistry con-firmed the diagnosis of a neuroendocrine tumor within apre-existing and well-differentiated sacrococcygeal ter-atoma that had been stable since childhood, now withpluripotent neuroendocrine secretion. Surgery would bechallenging and would be highly likely to lead to anileostomy and bladder dysfunction and a significant risk ofneurological sequelae. Targeted radiotherapy (to the solidcomponent of the teratoma) has been considered, but hasbeen declined by the patient, and at present, the tumor sizeremains stable.Well-differentiated neuroendocrine tumors arising intesticular teratomas are well recognized and usuallybehave in an indolent fashion [6]. Growth hormonesecretion in a mature ovarian teratoma has been previ-ously reported and this remains a possible source for theGH secretion [7]. In addition, ovarian teratomas cansecrete thyroid hormones from mature thyroid tissue(struma ovarii) leading to thyrotoxicosis in some cases[8], as well as the rarer ovarian carcinoid neoplasmssecreting 5HIAA [9]. Ectopic GHRH secretion has beenobserved in human pancreatic tumors [10], and in addi-tion, GHRH has some structural similarity with otherpeptides secreted within the gut such as VIP, glucagon,and GIP, which are known to weakly stimulate the releaseof growth hormone from the anterior pituitary [11].However, certain aspects of our case remain to be fullyexplained. For example, it is notable that there was nosign of pituitary hyperplasia histologically in the samplesent for analysis following transsphenoidal surgery (whichmight be anticipated in the presence of ectopic GHRHsecretion); in addition, unfortunately there was insuffi-cient tissue from the core biopsy of the sacrococcygealteratoma to permit staining for GHRH (and the patient’sIGF-I was normal at the time of biopsy). It is possiblethat due to tumor heterogeneity, GHRH or GH expres-sion was present in unsampled areas of the tumor. Never-theless, on balance, it seems most likely that our patient’sneuroendocrine tumor was the origin of his acromegaly.The cortisol hypersecretion (from ectopic ACTH) wasinadequately controlled by medication, necessitating bilat-eral adrenalectomy. Previous case reports have suggestedthe existence of ACTH-dependent Cushing’s syndrome ina sacrococcygeal teratoma [12, 13]. Our patient is likelyto have had a sacrococcygeal teratoma, which was stablefor decades, but later in life resulted in acromegaly, thenswitching to ACTH secretion (resulting in Cushing’s syn-drome) and serotonin secretion. In addition, it is possiblethat his current symptoms of breathlessness, hypo-glycemia, and fluctuant blood pressure are secondary tosecretion of other unidentified peptide(s). To our knowl-edge, this represents the first reported case of ACTH andserotonin secretion, and possible GHRH or GH cosecre-tion, from a sacrococcygeal teratoma in an adult.AcknowledgmentsDMB is supported by Orchid. MG is supported by theCambridge NIHR Biomedical Research Centre.1770 ª 2017 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.Pluripotent endocrinopathy in a teratoma T. Babiker et al.AuthorshipTB and AMB: involved in the patient’s care at the RoyalDevon and Exeter Hospital. WMD: involved in thepatient’s care at St Bartholomew’s Hospital. MG: con-sulted and in charge of methionine PET, EK, and DMB:provided histology reports. TB: prepared the manuscript.All authors contributed to the editing of the manuscript.Conflict of InterestThe authors have nothing to disclose.References1. Rindi, G., R. Arnold, F. T. Bosman, C. Capella, D. S.Klimstra, G. Kl€oppel, et al. 2010. Nomenclature andclassification of neuroendocrine neoplasms of the digestivesystem. WHO Classif. Tumours Dig. Syst. Ed. 4:13–14.2. Rosenberg, C., R. J. H. L. M. Van Gurp, E. Geelen, J. W.Oosterhuis, and L. H. J. Looijenga. 2000.Overrepresentation of the short arm of chromosome 12 isrelated to invasive growth of human testicular seminomasand nonseminomas. Oncogene 19:5858–5862.3. Huddart, S. N., J. R. Mann, P. Gornall, D. Pearson, A.Barrett, F. Raafat, et al. 1990. The UK Children’s CancerStudy Group: testicular malignant germ cell tumours1979–1988. J. Pediatr. Surg. 25:406–410.4. Mahour, G. H. 1988. Sacrococcygeal teratomas. CA CancerJ. Clin. 38:362–367.5. Emerson, R. E., C.-S. Kao, J. N. Eble, D. J. Grignon, M.Wang, S. Zhang, et al. 2017. Evidence of a dualhistogenetic pathway of sacrococcygeal teratomas.Histopathology 70:290–300.6. Wang, W. P., C. Guo, D. M. Berney, T. M. Ubright, D. E.Hansel, R. Shen, et al. 2010. Primary carcinoid tumors ofthe testis: a clinicopathologic study of 29 cases. Am. J.Surg. Pathol. 34:519–524.7. Ozkaya, M., Z. A. Sayiner, G. Kiran, K. Gul, I. Erkutlu,and U. Elboga. 2015. Ectopic acromegaly due to a growthhormone-secreting neuroendocrine-differentiated tumordeveloped from ovarian mature cystic teratoma. Wien.Klin. Wochenschr. 127:491–493.8. Kempers, R. D., M. B. Dockerty, D. L. Hoffman, and L.G. Bartholomew. 1970. Struma Ovarii—Ascitic,hyperthyroid, and asymptomatic syndromes. Ann. Intern.Med. 72:883.9. Davis, K. P., L. K. Hartmann, G. L. Keeney, and H.Shapiro. 1996. Primary ovarian carcinoid tumors. Gynecol.Oncol. 61:259–265.10. Esch, F. S., P. B€ohlen, N. C. Ling, P. E. Brazeau, W. B.Wehrenberg, M. O. Thorner, et al. 1982. characterizationof A 40 residue peptide from a human pancreatic tumorwith growth hormone releasing activity. Biochem. Biophys.Res. Commun. 109:152–158.11. Spiess, J., J. Rivier, and W. Vale. 1983. Characterization ofrat hypothalamic growth hormone-releasing factor. Nature303:532–535.12. Moreno-Fernandez, J., C. Gutierrez-Alcantara, M. A.Galvez Moreno, L. Jimenez-Reina, J. P. Casta~no, and P.Benito-Lopez. 2008. Corticotrophin-dependent Cushingsyndrome due to Sacrococcygeal Teratoma detected by[18F]fluorodeoxyglucose positron emission tomography. J.Clin. Endocrinol. Metab. 93:3282–3283.13. Wojcik, M., A. Kalicka-Kasperczyk, T. Luszawska-Kutrzeba, W. Balwierz, J. B. Starzyk, and M. Wojcik. 2015.The first description of metyrapone use in severe CushingSyndrome due to ectopic ACTH secretion in an infantwith immature sacrococcygeal teratoma. Neuro.Endocrinol. Lett. 36:653–655.ª 2017 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd. 1771T. Babiker et al. Pluripotent endocrinopathy in a teratoma

Acromegaly and Cushing's syndrome caused by a neuroendocrine tumor arising within a sacrococcygeal teratoma.

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Acromegaly and Cushing's syndrome caused by a neuroendocrine tumor arising within a sacrococcygeal teratoma.

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