Rare case of renal Ewing sarcoma presenting as ectopic Cushing syndrome in a 12-year-old girl

Abstract

We present a 12-year-old girl with recent onset weight gain and purple striae over the abdomen. Examination revealed her to be hypertensive. On evaluation for Cushing syndrome (CS), her cortisol and adrenocorticotropic hormone (ACTH) were found to be high. MRI brain showed a suspicious lesion (thought to be pituitary microadenoma). Inferior petrosal sinus sampling was not conclusive of pituitary source of ACTH. High dose dexamethasone suppression test confirmed an ectopic source of ACTH secretion and CT scan revealed a mass in the right kidney which was laparoscopically excised. Histopathology and immunohistochemistry confirmed Ewing sarcoma. Our case highlights the rare presentation of renal Ewing sarcoma (RES) as CS. To the best of our knowledge, this is only the second case report of RES/primitive neuroectodermal tumour of the kidney presenting as CS in paediatric age group and first with a concomitant pituitary incidentaloma.

Background

Ewing sarcoma (ES), the second most common malignant bone tumour, first described by Dr James Ewing to be characteristically present in the diaphysis of long bones. The annual incidence of ES is 2.93 children per 1 000 000.¹ Though it is most commonly osseous in origin, it may arise from other tissues in the body. Renal Ewing sarcoma (RES) is a rare primitive neuroectodermal tumour which was first described by Seemayer et al, in 1975. It results from translocation mutation fusing the EWS and FLI1 genes of chromosome 22 and chromosome 11, respectively.² Typical clinical presentation of RES involves flank pain and haematuria.³

To the best of our knowledge, this is the second reported case of paediatric RES presenting as CS. We describe a 12-year-old girl who presented with recent onset weight gain and purple striae over the abdomen. On evaluation, the patient was found to have an adrenocorticotropic hormone (ACTH) secreting renal mass; MRI brain showed a suspicious lesion which was thought to be a pituitary microadenoma. Histopathology on the renal mass revealed it to be a primitive neuroectodermal tumour of the kidney (PNET)/renal Ewing sarcoma (RES). The case highlights the diagnostic course of rare presentation of RES as CS with concomitant pituitary incidentaloma.

Case presentation

A 12-year-old girl was referred to our tertiary level care paediatric endocrine unit with complaints of recent onset weight gain (12 kg over 4 months). The mother had noticed purple striae over the abdomen, fine hair and acne appearing over the forehead, cheeks and upper back. She was born of a non-consanguineous marriage with a birth weight of 3.5 kg (vaginal delivery at term). She has no siblings. There was no history of similar complaints in the family.

On anthropometric evaluation, her height was 152 cm ((Z score 0.5), in the target range for mid-parental height of 161 cm (Z score 0.5)), weight of 68 kg (Z score 2.38) and body mass index of 29.4 (Z score 2.5). On examination, the patient was found to have moon face, facial plethora, buffalo hump and violaceous striae over the abdomen (figure 1). On recording vitals, heart rate was 86/min and blood pressure was 140/100 mm Hg (stage 2 hypertension according to Manuraj et al).⁴ Sexual maturity rating was stage 3 according to Tanner staging.⁵

Figure 1.

A 12-year-old girl with violaceous striae over the flanks.

The patient was investigated on clinical suspicion of Cushing syndrome (CS). At 08:00, cortisol and ACTH were found to be 25 mcg/dL (normal value: 5–25 mcg/dL) and 126 pg/mL (normal value: 10–60 pg/mL), respectively. Cortisol and ACTH were not suppressed after overnight dexamethasone suppression test (cortisol: 17 mcg/dL and ACTH: 108 pg/mL). Urinary free cortisol was high (above measurable range). Random blood glucose was 144 mg/dL (8 nmol/mL), serum sodium was 138 mEq/L and potassium was 3.3 mEq/L. MRI of the brain showed a focal area of less enhancement measuring about 2 mm in the left half of the pituitary gland on dynamic postcontrast study which was interpreted as a possible microadenoma (figure 2). Inferior petrosal sinus sampling (IPSS) was not conclusive of pituitary source of ACTH, the findings are summarised in table 1 (figure 3).⁶

Figure 2.

Pituitary incidentaloma in a 12-year-old girl with Cushing syndrome under evaluation.

Table 1.

Findings of inferior petrosal sinus sampling

Parameter	Peripheral	Right petrosal	Left petrosal	Ratio (IPS:Peripheral)
ACTH (7.2–63 pg/mL)	53.8	54.39	63	Right: 1.01 Left: 1.17
Prolactin (ng/mL)	2.5	2.55	4.62	Right: Petrosal: peripheral prolactin: 1 (ACTH: prolactin): 1.01 Left: Petrosal: peripheral prolactin: 1.8 ACTH: prolactin: 0.6

ACTH, Adrenocorticotropic Hormone; IPS, Inferior Petrosal Sinus.

Figure 3.

Inferior petrosal sinus sampling in a 12-year-old girl Cushing syndrome under evaluation.

A high dose dexamethasone suppression test (HDDST, after 8 doses of 2 mg dexamethasone) was performed. The cortisol and ACTH failed to suppress, indicating an ectopic source of ACTH. CT scan revealed a heterogeneous mass lesion of 70×67×82 mm in the maximum craniocaudal, anteroposterior and transverse axis at the lower pole of the right kidney. Gallium 68 dotatate scan showed a large mass in the interpolar region of the right kidney with weak octreotide receptor expression and F18 whole body PET CT scan showed flurodeoxyglucose avid mass in interpolar region of right kidney and small ametabolic regional lymph nodes (figures 4 and 5). There was no evidence of distant organ involvement on both the scans.

Figure 4.

A large mass in the interpolar region of the right kidney with weak octreotide receptor expression (gallium 68 dotatate scan).

Figure 5.

Flurodeoxyglucose avid mass in interpolar region of right kidney and small ametabolic regional lymph nodes (F18 whole body PET CT scan).

ACE inhibitor and beta-blocker (enalapril: 0.1 mg/kg/day, propranolol: 1 mg/kg/day) were given to achieve a normotensive state. A laparoscopic excision of the tumour was undertaken (10% of the right kidney could be salvaged). The surgery was uneventful, and the patient received a stress dose of intravenous hydrocortisone during the surgery and maintenance dose during the postoperative period. Histopathology of the mass revealed primitive neuroectodermal tumour of the kidney (EWS), the renal capsule was intact and no surrounding structures were involved. On immunohistochemistry (2325/21G) the neoplastic cells expressed cytokeratin, synaptophysin, Mic 2 and NKX 2.2 and were immunonegative for chromogranin A, desmin, BCOR, SATB2 and TLE-1.

On evaluating the endocrine axis after a week of the surgery, the ACTH and cortisol were found to be within normal range and the steroid was tapered and discontinued. Also, the patient was normotensive without antihypertensive medication and other features of hypercortisolism improved after surgery. She is presently receiving chemotherapy as per oncologist’s advice.

Outcome and follow-up

There is clinical improvement of the Cushingoid features after surgery.

The patient is presently receiving chemotherapy and does not require antihypertensives.

Discussion

The Ewing sarcoma family of tumours is the second most common bone malignancy in children and adolescents.⁷ ES was first described by John Ewing in 1918 as an osseous tumour mostly encountered in the diaphysis of long bones. It is a neuroendocrine tumour which originates from the neural crest cells that invaginate into the kidney during embryonic development.³ Another theory suggests that embryonic neural crest cells migrate into the kidney and undergo tumorigenesis.³ RES was first described by Seemayer et al, in 1975 and since then, has been described sporadically. They belong to the family of tumours called primitive neuroectoderm tumours. The term peripheral primitive neuroectoderm tumours (PNETs) encompasses peripherally located tumours. ES differs from PNET due to its lack of neuroectodermal features.⁸

RES is rare and usually presents with flank pain, palpable mass in the abdomen and occasionally haematuria.³ In this case, the patient presented with features of CS and was evaluated accordingly. There has been only one previous case report of an 18-month-old patient with similar features which was found to be PNET on evaluation.⁹ In our patient on confirmation of CS, the high ACTH pointed towards Cushing disease (CD) or ectopic ACTH secretion. Given the epidemiology of CD and EAS in paediatric age group, MRI brain was undertaken which showed a small mass (2 mm) in the pituitary.¹⁰ Given the rarity of pituitary incidentalomas in paediatric age group (10%–20% in adults), IPSS was undertaken which failed to confirm pituitary source of ACTH and, hence, HDDST was undertaken which indicated an ectopic source of ACTH production. Further, imaging revealed a mass in the right kidney, which on histopathology was confirmed to be the source of ACTH production (neuroendocrine tumour).

Histologically, RES is composed of uniform small round cells. ES is known to stain positive for CD-99 and FLI-1. CD45, WT-1 and Desmin have been reported as negative in literature.¹¹ In this case, the tumour tissue stained strongly positive for CD-99 suggesting ES. ES/PNET is characterised by fixed chromosomal translocation t (11:22) between the genes EWS (22q12) and FLI-1 (11q24), detected by fluorescence in situ hybridisation.¹² The limitation of this case report was unavailability of the histopathology slide.

There is lack of consensus on treatment of RES. Surgical excision of tumour followed by chemotherapy for prolonged periods is the usual standard of care. In this case, the tumour was laparoscopically excised, and the patient is presently on chemotherapy. Radiotherapy has been used in enlarged locoregional lymph nodes. It is important to note that biopsy is not indicated as it will delay the resection of tumour and may cause seeding of peritoneum with tumour tissue. Despite aggressive approach to treatment, the prognosis of RES remains poor. The most common sites of metastasis are lungs, liver and bone. Median survival reported in advanced disease is only 5.6 months.³ Prognosis is known to be better when there is no distant metastasis at diagnosis. In this case, there was no evidence of distant metastasis or regional lymph node involvement. Also, the renal capsule was intact. The limitation here is the unavailability of the image of our patient with RES presented as ectopic Cushing rather than the typical presentation of flank pain and mass. A high index of suspicion is required for coming to the diagnosis of RES in such atypical cases.

Learning points.

• A lesion less than 5 mm on MRI pituitary must not be concluded as Cushing disease until further evaluation as it may be an incidentaloma.

• High dose dexamethasone suppression test yields a good diagnostic response to differentiate central from peripheral source of adrenocorticotropic hormone (ACTH) secretion and is desirable to be undertaken before embarking on inferior petrosal sinus sampling.

• Though rare, ectopic ACTH secretion must be considered in ACTH dependent Cushing syndrome.

Ethics statements

Patient consent for publication

Consent obtained from parent(s)/guardian(s).