Ectopic ACTH Syndrome and Hypothyroidism Due to Right Renal Small Round Blue Cell Tumor: A Case Report

Background: Small round blue cell malignancies are rare and highly aggressive tumors that are commonly located in the soft tissues or axial bones of the bone or trunk and are particularly rare in the kidney. The common cause of ectopic ACTH syndrome is pulmonary neuroendocrine tumors, such as small cell carcinomas and carcinoid tumors. Here, we present an unusual case of ectopic ACTH syndrome and hypothyroidism caused by small round blue cell tumor of the right kidney. Case presentation: A 19-year-old girl presented with a history of right lumbar pain and discomfort for 2 months, aggravated for 2 days. Abdominal contrast-enhanced computed tomography and computed tomography angiography showed right suprarenal pole occupancy with subepithelial hemorrhage. Preoperative hormone levels including plasma total cortisol (PTC), adrenocorticotrophic hormone (ACTH) and thyroid hormone measurements were abnormal, indicating that the patient had Cushing syndrome and hypothyroidism. The patient underwent right radical nephrectomy. Histopathological analysis revealed a renal small round blue cell tumor (consistent with a primitive neuroectodermal tumor), with positive immunohistochemistry for CD99 and Ki67 (about 10%) and molecular pathology for EWSR1 gene fusions. PTC, ACTH and thyroid hormone returned to normal after surgery. Conclusions: We report a rare ectopic ACTH syndrome and hypothyroidism due to renal small round blue cell tumor. The clinical manifestation of renal small round blue cell tumor is non-specic and the diagnosis relies on pathological morphology, immunohistochemistry and fusion gene detection. At present, surgery combined with radiotherapy and chemotherapy is used in the treatment, but the prognosis is still not optimistic.

normal after surgery.
Conclusions: We report a rare ectopic ACTH syndrome and hypothyroidism due to renal small round blue cell tumor. The clinical manifestation of renal small round blue cell tumor is non-speci c and the diagnosis relies on pathological morphology, immunohistochemistry and fusion gene detection. At present, surgery combined with radiotherapy and chemotherapy is used in the treatment, but the prognosis is still not optimistic.
Background Small round blue cell tumors are a rare class of malignant tumors that can occur in all parts of the body, most commonly in bone or soft tissues in the trunk or axial bones, and rarely in the kidney (1,2). Small round blue cell tumors are histologically characterized by proliferation of small round tumor cells with sparse cytoplasm, which are often di cult to distinguish by standard histology or immunohistochemistry (3,4). The disease usually has an insidious onset, rapid progress, easy recurrence and metastasis, and poor prognosis. Patients with small round blue cell tumors require rapid treatment (5).
Cushing syndrome caused by excessive secretion of ACTH from tumor tissues other than the pituitary gland is called ectopic ACTH syndrome, accounting for 10%-20% of Cushing syndrome (6). The common causes of ectopic ACTH syndrome are lung or bronchial tumors, followed by thymic and pancreatic tumors (7). Herein, we introduce a rare case of ectopic Cushing syndrome and hypothyroidism caused by a malignant tumor of small round blue cell in the right kidney.

Case Presentation
A 19-year-old girl presented to our hospital with a history of right lumbar pain and discomfort for 2 months and aggravated for 2 days. The patient felt the right waist pain 2 months ago, which was persistent dull pain, and increased right-sided back pain after running 2 days ago. Abdominal computed tomography (CT) showed right renal hamartoma with hemorrhage in the local hospital. The patient had no signi cant medical history and was not receiving any medication at the time of referral. Of note in the history was that the patient discovered facial swelling, increased acne on the face and back, and scanty menstruation six months ago. Upon admission, physical examination revealed concentric obesity and positive percussion pain in the right costal horn.

Imaging Examinations
Abdominal imaging with contrast-enhanced computed tomography and computed tomography angiography (Sep 5) showed right suprarenal pole occupancy (size 9.4cm*9.9 cm) with subepithelial hemorrhage, right renal artery branch supplied blood, and the right portal lymph node enlargement (Fig. 1).

Treatment
Re-examination of the patient's blood routine, renal function and protein level showed that the infection index further increased, and the renal function and protein level decreased. The patient received double J tube implantation under left ureteroscope plus right radical nephrectomy plus clearance of right perirenal hematoma plus lysis of right perirenal adhesion on Sep 8. The patients were transferred to ICU monitoring and treatment after surgery.

Pathology
The maximum diameter of the tumor was 8 cm. The tumor involved renal parenchyma, perirenal adipose tissue and adrenal gland, and a carcinoma thrombus was seen in the vasculature. Under light microscope, the tumor cells were lamellar, composed of a large number of small round cells with relatively uniform morphology and little cytoplasm (Fig. 2). The immunohistochemical results were positive for CD99 and Ki67 (about 10%), while Vim, Syn, FSH and ACTH were negative (Fig. 3). EWSRI gene fusion was detected by uorescence in situ hybridization (FISH) (Fig. 4). According to the results of postoperative pathology and molecular pathological examination, the nally diagnosed was renal small round blue cell tumor (consistent with primitive neuroectodermal tumor (PNET)).

Follow-up
The blood routine, renal function and protein levels of the patients showed a trend of improvement for three consecutive days after surgery, ACTH and plasma total cortisol (PTC) decreased to normal, and thyroid hormones tended to normal ( Table 1). The patient's facial swelling was reduced and the acne on her face and back subsided. However, three weeks after surgery, the patient died while preparing for further chemotherapy.

Discussion And Conclusions
PNET is a highly malignant small round blue cell tumor with neural differentiation. According to the location, PNET can be divided into central PNET (cPNET) and peripheral PNET (pPNET) (8). PNET usually occurs in children and adolescents, and the most common site is bone or soft tissue in the trunk or axial bone. PNET in the genitourinary system is relatively rare, and even rarer in the kidney (9). Renal PNET is a type of pPNET with a median age of about 27 years old, and is slightly more common in males (10).
The clinical manifestations of renal PNET are non-speci c. The gross section of tumor tissue was gray, grayish brown and tender, accompanied by hemorrhage, necrosis and cystic degeneration. In the histological examination of renal PNET, the tumor cells were arranged in nest shape, and Homer-Wright rosettes were seen. Homer-Wright rosettes are one of the main histological bases for the diagnosis of renal PNET (11). The diagnosis of renal PNET mainly depends on pathological examination. With the improvement of immunohistochemical techniques, immunohistochemistry has become an important basis for pathological diagnosis of renal PNET (12). CD99 is a monoclonal antibody that recognizes p30/32 glycoprotein and can be detected in almost all renal PNET (13). In addition, some cases expressed vimentin, NSE, S-100 and Syn (14). There is no standardized criteria for the pathological diagnosis of renal PNET, which is generally considered to be consistent with(15): (1) Homer-Wright rosettes under light microscope; (2) positivity for CD99 and other neural markers (at least 2 kinds).
In recent years, it has been found that 90%-95% of PNET have a t(11; 22) (q24; q12) chromosome translocation, leading to the production of the EWS/FLI-1 fusion gene (16). It has been shown that the FISH method detects EWSR1 gene fusions with a sensitivity of 92.3% and a speci city of 100% (17). Therefore, the FISH method to detect fusion genes formed by PNET-speci c chromosomal translocations has greater diagnostic and differential diagnostic value. In summary, the diagnosis of renal PNET should be comprehensively judged by light microscopic morphology, immunohistochemistry and FISH method. In the pathological diagnosis of this patient, immunohistochemistry showed CD99 and Ki67 positivity, FISH showed EWSR1 gene fusion, and the diagnosis of small round blue cell tumor was con rmed.
According to previous reports, ectopic ACTH syndrome is primarily associated with small cell or lung carcinoid carcinoma, and also be associated with mediastinum, pancreases, thymus, and pheochromocytoma (18)(19)(20). Neuroendocrine tumors rarely produce excessive ACTH and cause ectopic ACTH syndrome. To our knowledge, we describe the rst case of ectopic ACTH syndrome and hypothyroidism caused by a renal small round blue cell tumor. Although our patient received radical nephrectomy treatment, postoperative ACTH and PTC decreased to normal, and thyroid hormones tended to normalize. The patient's facial swelling was alleviated and the acne on the face and back subsided. However, due to the highly malignant and aggressive nature of the tumor, the patient died in preparation for further chemotherapy.
Renal PNET is more prone to recurrence and metastasis than other renal tumors, with the most common site of metastasis being the lung, followed by the liver and bone (21 Consent for publication Written consent was obtained from the patient to publish this case report.
Availability of data and materials The dataset used during the study are available from the corresponding author on a reasonable request.
Con icts of Interest We declare that there are no con icts of interest between authors.