Introduction: Primitive neuroectodermal tumors (PNET) form a group of tumors defined by their appearance that are thought to develop from primitive (undifferentiated) nerve cells in the brain. They are rare tumors and their incidence is not well defined. Case presentation: An 18-month-old male presenting with typical Cushingoid appearance (moon face, central obesity, hirsutism and growth arrest) was admitted for evaluation of endocrine problems. Subsequent laboratory studies revealed markedly elevated adrenocorticotropic (ACTH) and cortisol levels, as well as a hypokalemic metabolic alkalosis, these data are consistent with the diagnosis of Cushing's disease. He was treated with metyrapone to control hypercortisolemia. One month and a half later, a mass was detected in the abdomen by ultrasonography. An abdominal Computed tomography confirmed a large heterogeneous retroperitoneal mass with a significant amount of extension into surrounding structures which was removed by laparoscopic abdominal surgery. The patient's symptoms completely resolved and the ACTH and cortisol levels were also greatly reduced. Histologically, the tumor tissue consistent with the diagnosis of the retroperitoneal primitive neuroectodermal tumor which was confirmed immunohistochemically. This case demonstrates the successful diagnosis and treatment of a rare neoplasm. Conclusion: This is the first rare case with ectopic ACTH syndrome caused by the peripheral primitive neuroectodermal tumor. Â© 201

bahoush, G.

Rahbar, M.

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Contents lists available at ScienceDirectAnnals of Medicine and Surgeryjournal homepage: www.elsevier.com/locate/amsuCase reportPeripheral primitive neuroectodermal tumor associated with paraneoplasticCushing's syndrome: The rare caseMahtab Rahbara,∗, Maryam Rahbarb, Gholamreza bahoushaa Iran University of Medical Science, Tehran, Iranb Tehran Medical Science of University, Tehran, IranA R T I C L E I N F OKeywords:Peripheral primitive neuroectodermal tumorCushing's diseaseParaneoplastic syndromeA B S T R A C TIntroduction: Primitive neuroectodermal tumors (PNET) form a group of tumors defined by their appearance thatare thought to develop from primitive (undifferentiated) nerve cells in the brain. They are rare tumors and theirincidence is not well defined.Case presentation: An 18-month-old male presenting with typical Cushingoid appearance (moon face, centralobesity, hirsutism and growth arrest) was admitted for evaluation of endocrine problems. Subsequent laboratorystudies revealed markedly elevated adrenocorticotropic (ACTH) and cortisol levels, as well as a hypokalemicmetabolic alkalosis, these data are consistent with the diagnosis of Cushing's disease. He was treated withmetyrapone to control hypercortisolemia. One month and a half later, a mass was detected in the abdomen byultrasonography. An abdominal Computed tomography confirmed a large heterogeneous retroperitoneal masswith a significant amount of extension into surrounding structures which was removed by laparoscopic ab-dominal surgery. The patient's symptoms completely resolved and the ACTH and cortisol levels were also greatlyreduced. Histologically, the tumor tissue consistent with the diagnosis of the retroperitoneal primitive neu-roectodermal tumor which was confirmed immunohistochemically. This case demonstrates the successful di-agnosis and treatment of a rare neoplasm.Conclusion: This is the first rare case with ectopic ACTH syndrome caused by the peripheral primitive neu-roectodermal tumor.1. IntroductionPeripheral primitive neuroectodermal tumor (PNET) is an un-common tumor and the overall incidence is 1% of all sarcomas [1].Primitive neuroectodermal tumors (PNETs) are rare small round cellneoplasms, first described in 1918 by Stout [2] as a malignant tumorarising from major nerve [3]. This tumor can occur at any age, althoughthe peak age incidence is during adolescence and young adulthood andthe tumors are rarely observed in children< 3 years old. The incidenceof peripheral PNET in the abdomen and pelvis, including the retro-peritoneum, is about 14% of all peripheral PNETs [4]. Cushing's syn-drome is a disorder of hypercortisolism which has a characteristic ap-pearance (moon facies, buffalo hump, truncal obesity, and purplestriae). Furthermore, it is associated with a variety of organ dysfunc-tions including cardiovascular, endocrine, neural, gastrointestinal, skin,and musculoskeletal. Ectopic secretion of ACTH accounts for ∼10% ofCushing's syndrome etiologies [5–8].The following case is that of an 18months-old Iranian boy presenting with Cushing's syndrome due toACTH-secreting peripheral PNET. Our case is very rare in its pre-sentation.2. Case presentationIn september2017, an 18-month-old male admitted in endocrinedepartment with symptoms of moon face, general weakness, centralobesity, growth arrest and short stature of 5 months duration. Onphysical exam, the patient was noted to have 1 + pitting edema on hislower extremities bilaterally and hirsutism in back of trunk. At the timeof presentation, he did not appear severely cushingoid appearance andhis blood pressure was (115/61 mm Hg). Laboratory results revealedhighly elevated ACTH and cortisol levels (ACTH = 731 pg/mL; AMcortisol = 142.8 μg/dL; 24-h urine cortisol 12743.5μg/24 hours totalvolume). In addition, the patient was also hypokalemic (3.0 mEq/L)and had a metabolic alkalosis (pH = 7.89, HCO3 = 41 mEq/L).Dexamethasone suppression test was considered: however, in the pre-sence of very high ACTH and cortisol levels, hypokalemia, andhttps://doi.org/10.1016/j.amsu.2018.11.018Received 17 September 2018; Accepted 25 November 2018∗ Corresponding author. Tel.: +98 2122435412.E-mail addresses: rahbar.m@iums.ac.ir (M. Rahbar), rahbar_maryam81@yahoo.com (M. Rahbar), bahoush04@yahoo.com (G. bahoush).Annals of Medicine and Surgery 37 (2019) 21–242049-0801/ © 2018 Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/BY/4.0/).Tmetabolic alkalosis, as well as clinical findings, a primary pituitarytumor or an ectopic ACTH syndrome was suspected. Brain MRI wasnegative for primary pituitary tumor. Abdominal ultrasonography(USG) showed a solid, calcified heterogeneous mass measuring57 × 46 × 36 mm in front of anteromedial of right kidney near toinferior pole. A Doppler ultrasound test showed the blood flow throughinferior vena cava (IVC) restricted by pressure effect of tumor. Contrast-enhanced computed tomography abdomen showed large lobulated,necrotic and calcified hypodense enhancing mass measuring47.6 × 44.3 mm in the largest diameters that extending from anteriorof right kidney to retroperitoneum and involving retroperitoneal space.The lesion was abutting the IVC, displacing it laterally (Fig. 1) TheUSG/CT appearance of the mass, in combination with the clinical andlaboratory findings, was suspicious for neuroblastoma or pPNET. In-formed consent was obtained from parents prior to surgery. Total re-section of mass was performed by laparoscopic abdominal surgery.After surgery, his metabolic abnormalities were controlled. Grossly, thetumor was brownish, soft and multilobulated. Gross examination of thespecimen sent to us revealed a soft tissue mass measuring about47×42×37 mm, cut surface of which revealed an encapsulatedcreamy to brownish mass with lobulated and variegated appearancewith solid and necrotic areas with foci of calcification (Fig. 2). Onmicroscopic examination, there were lobules of tumor cells separatedby fibrous septa. The tumor cells comprised of small cells with roundvesicular nuclei, inconspicuous nucleoli, scanty eosinophilic cytoplasmwith frequent homer wright rosettes and pseudorosettes (Fig. 3). Theimmunohistochemical evaluation revealed a diffuse CD99 and vimentinpositivity in the cytoplasm of the neoplastic cells. Pan keratin, cyto-keratin AE1/AE3, myogenin and CD45 were negative. The S-100 pro-tein was weakly positive in tumor cells. Ki67 immunostain shows about65% immunoreactivity. Also, there were focal expression of synapto-physin and ACTH (Fig. 3). These findings represent an ACTH-secretingPNET. Following the operation, his ACTH level decreased to 22 pg/mL.Ki67 immunostain shows about 65% immunoreactivity. He was dis-charged on hydrocortisone 5 mg in the morning and 5mg in the eveningfor secondary glucocorticoid deficiency because of prolonged ectopicACTH secretion. When the patient finished the hydrocortisone course,he maintained a normal ACTH, morning plasma cortisol, and urinecortisol levels. Furthermore, his Cushing's syndrome symptoms com-pletely resolved.3. DiscussionApproximately 5%–10% of cases of Cushing syndrome (hy-percortisolism) are paraneoplastic.[9] Paraneoplastic Cushing's syn-drome has been attributed to ectopic adrenocorticotropin (ACTH)secretion, which may result in several types of tumors, including car-cinoid and pancreatic neuroendocrine tumors [10], small cell lungcancer and thyroid medullary carcinoma [11], Wilms tumor [12],prostatic cancer [13,14], neuroblastoma [11], and thymus tumor[15,16]. Patients often present with symptoms of paraneoplasticCushing syndrome before a cancer diagnosis is made. Similarly, relapseof paraneoplastic Cushing syndrome may herald tumor recurrence[12].Paraneoplastic Cushing syndrome arises from tumor secretion ofadrenocorticotropic hormone or corticotropin-releasing factor [9,13].The diagnosis of ectopic ACTH syndrome secondary to esthesioneuro-blastoma was established based on the presence of ACTH seen on im-munohistochemical staining of the tumor, the disappearance of symp-toms, as well as a decrease and normalization of plasma ACTH andcortisol levels after resection of the tumor. Peripheral primitive neu-roectodermal tumor (pPNET) is a group of malignant small round celltumor with neural crest origin that arises outside the central andsympathetic nervous system [17].They belong to the Ewing sarcomaFig. 1. Contrast enhanced computed tomography abdomen showed large lobulated necrotic hypodense enhancing lesion involving part of retroperitoneal space.Fig. 2. Gross image of a renal primitive neuroectodermal tumor. This specimenis notable for a variegated appearance. Select areas of the tumor feature a tan/brown or dark brown/red coloration, whereas other sections of the tumorfeature a more yellow appearance, helping to illustrate the range of colorationobservable on gross examination. This specimen is also notable for its lobulatedappearance.M. Rahbar et al. Annals of Medicine and Surgery 37 (2019) 21–2422family of tumors with similar histologic and immunohistochemicalcharacteristics [18]. Peripheral PNETs are rare in the abdomen [17].This tumor rarely presents as an organ-derived neoplasm [19]. Care-fully the selected immunohistochemical panel is important for differ-entiating this tumor from other small round cell tumors in abdomenssuch as rhabdomyosarcoma, neuroblastoma, clear cell sarcoma of thekidney, non-Hodgkin lymphoma and Ewing's sarcoma. Im-munohistochemically, PNET cells express vimentin, NSE, and CD99[20]. The positive reactivity to CD99 is a clue for PNET diagnosis [19].Review of radiologic findings showed that most cases of retroperitonealPNETs in the literature, similar to our case, presented as a large masswith areas of necrosis and heterogeneous enhancement in contrastimaging. Some cases had areas of hemorrhage, but in our case, therewas no hemorrhage. Our case had several foci of curvilinear calcifica-tion compared to other case reports, in which calcification was a rarefinding (one of ten cases in a case series) [21]. Organ invasion anddisplacement, such as direct invasion or displacement of the pancreas,kidney, spleen, and stomach was present in some cases, including ourcase but our case didn't show [21].There was no clinical or imagingevidence of venous thrombosis in the inferior vena cava (IVC), whilevenous thrombosis has been detected in other patients [20,21]. Ap-proximately 20% of the patients present with metastatic disease; out ofwhich 44% present with lung metastases only, 51% have bone or bonemarrow involvement (with or without lung metastases) and less than5% present with metastases in other organs. There is no evidence ofinvasion or metastasis in our case. Also, splitting calcification is seenrarely [22]. However, our case was associated with Cushing's syndromewhich was a paraneoplastic syndrome. Thus, this is the first rare casewith ectopic ACTH syndrome caused by the peripheral primitive neu-roectodermal tumor. Ectopic ACTH syndrome due to pPNET is ex-tremely uncommon with no case being discussed in the literature.4. ConclusionpPNET associated with Cushing's syndrome is extremely rare. This isthe first report that didn't report cases in the literature. This reportintends to highlight that PNET should be suspected whenever a patientpresents with paraneoplastic Cushing's syndrome and may often beconfused with other tumors presented with the cushingoid syndrome.Early diagnosis is important to ensure timely surgical resection fol-lowed by appropriate chemotherapy and/or radiotherapy.Patient consentThe parents have given consent for possible publication of this casereport and accompanying images.Provenance and peer reviewNot commissioned, externally peer reviewed.Ethical approvalEthics approval was not applicable.Sources of fundingNo external funding was required for this study.Author contributionMahtab rahbar and maryam rahbar: Data collection, data analysis &interpretation and writing the paper. Gholamreza Bahoush: StudyFig. 3. A, Hematoxylin and eosin features of thetumor (original magnification 40 ×): sheets ofpoorly differentiated, monotonous, ovoid cells, witha high nuclear to cytoplasmic ratio. Homer-Wrightrosettes were common. B, Tumor cells with necroticareas and foci of calcifications .C, Immunoperoxidasefor CD99 (40×) showed predominantly membra-nous staining of tumor cells composed of small roundcells with round nuclei and scant cytoplasm arrangedin cohesive lobules. D, Immunoperoxidase for ACTH(10×) showed Diffuse cytoplasmic staining of tumorcells.M. Rahbar et al. Annals of Medicine and Surgery 37 (2019) 21–2423concept & design, data collection, data analysis or interpretation,writing the paper.Conflicts of interestThe authors declare that they have no competing interests.Trial registry numberResearch Registry number:4291.GuarantorMahtab Rahbar.AcknowledgmentsAll authors thank the Ali Asghar hospital staff for support of thisstudy.Appendix A. Supplementary dataSupplementary data to this article can be found online at https://doi.org/10.1016/j.amsu.2018.11.018oReferences[1] F. Maccioni, C. Della Rocca, P.F. Salvi, A.M. Manicone, A. Ascarelli, F. Longo, et al.,Malignant peripheral neuroectodermal tumor (MPNET) of the kidney, Abdom.Imag. 25 (2000) 103–106.[2] A.P. Stout, A tumor of the ulnar nerve, Proc. NY Pathol. Soc. 18 (1918) 2–11.[3] S.S. Desai, N.A. Jambhekar, Pathology of Ewing's sarcoma/PNET: current opinionand emerging concepts, Indian J. Orthop. 44 (2010) 363–368.[4] H. Jurgens, V. Bier, D. Harms, J. Beck, W. Brandeis, W. Etspuler, et al., Malignantperipheral neuroectodermal tumors: a retrospective analysis of 42 patients, Cancer61 (1988) 349–357.[5] I. Tazi, S. Zafad, A. Madani, et al., Askin tumor: a case report with literature review,Cancer Radiother. 13 (2009) 771–774.[6] H.C. Song, N. Sun, W.P. Zhang, C.R. Huang, Primary Ewing's sarcoma/primitiveneuroectodermal tumor of the urogenital tract in children, Chin. Med. J. (Engl) 125(2012) 932–936.[7] S. Heikaus, K.L. Schaefer, J. Eucker, et al., Primary primitive neuroectodermaltumor/Ewing's tumor of the testis in a 46-year-old man-differential diagnosis andreview of the literature, Hum. Pathol. 40 (2009) 893–897.[8] A.K. Hormozi, M.R. Ghazisaidi, S.N. Hosseini, Unusual presentation of peripheralprimitive neuroectodermal tumor of the maxilla, J. Craniofac. Surg. 21 (2010)1761–1763.[9] S.L. Barbosa, P. Rodien, S. Leboulleux, et al., Ectopic adrenocorticotropic hormone-syndrome in medullary carcinoma of the thyroid: a retrospective analysis and re-view of the literature, Thyroid 15 (2005) 618–623.[10] J.D. Teale, V. Marks, Glucocorticoid therapy suppresses abnormal secretion of bigIGF-II by non-islet cell tumors inducing hypoglycemia (NICTH), Clin. Endocrinol.49 (1998) 491–498.[11] B.L. Wajchenberg, B.B. Mendonca, B. Liberman, M.A. Pereira, P.C. Carneiro,A. Wakamatsu, M.A. Kirschner, Ectopic adrenocorticotropic hormone syndrome,Endocr. Rev. 15 (1994) 752–787.[12] U. Morandi, C. Casali, G. Rossi, Bronchial typical carcinoid tumors, Semin. Thorac.Cardiovasc. Surg. 18 (2006) 191–198.[13] D.A. Teves, Clinical approach of Cushing syndrome resulting from the ACTH-pro-ducing metastatic neuroendocrine tumor, Endocrinololgist 15 (2005) 401–404.[14] S. Nimalasena, A. Freeman, S. Harland, Paraneoplastic Cushing's syndrome inprostate cancer: a difficult management problem, BJU Int. 101 (2008) 424–427.[15] L.K. Nieman, Medical therapy of Cushing's disease, Pituitary 5 (2002) 77–82.[16] M.K. Nayar, M.G. Lombard, N.J. Furlong, S.J. McNulty, K.J. Hardy, J. Vora,Diagnosis and management of non-islet cell tumor hypoglycemia: case series andreview of the literature, Endocrinololgist 16 (2006) 227–230.[17] J. Gong, Y. Zhang, M. Zuo, Z. Yang, D. Zang, S. Bao, et al., Imaging findings ofabdominal peripheral primitive neuroectodermal tumor: report of four cases withpathological correlation, Clin. Imag. 33 (2009) 196–199.[18] H.E. Grier, The Ewing family of tumors. Ewing's sarcoma and primitive neu-roectodermal tumors, Pediatr. Clin. 44 (1997) 991–1004.[19] L.W. Baijens, J.J. Manni, Paraneoplastic syndromes in patients with primary ma-lignancies of the head and neck: four cases and a review of the literature, Eur. Arch.Oto-Rhino-Laryngol. 263 (2006) 32–36.[20] A.F. Stewart, Hypercalcemia associated with cancer, N. Engl. J. Med. 352 (2005)373–379.[21] H. Raftopoulos, Diagnosis and management of hyponatremia in cancer patients,Support. Care Canc. 15 (2007) 1341–1347.[22] Q. Badar, N. Ali, N. Abbasi, S. Ashraf, F. Karsan, R. Hashmi, Ewing's sarcoma/PNETof kidney in 13-year-old girl, J. Pakistan Med. Assoc. 60 (2010) 314–315.M. Rahbar et al. Annals of Medicine and Surgery 37 (2019) 21–2424

Peripheral primitive neuroectodermal tumor associated with paraneoplastic Cushing's syndrome: The rare case

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Peripheral primitive neuroectodermal tumor associated with paraneoplastic Cushing's syndrome: The rare case

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