justin ewing cystic fibrosis case study

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Case report: Three adult brothers with cystic fibrosis (delF508-delF508) maintain unusually preserved clinical profile in the absence of standard CF care

We present three cases in this report. Three adult brothers, homozygous for the delF508 cystic fibrosis mutation, have maintained an unusually preserved clinical condition even though they did not attend a CF Clinic during their childhood, do not attend a CF Clinic now, and do not follow standard CF care guidelines. The brothers use an alternative CF treatment regimen on which they have maintained normal lung function, height/weight, and bloodwork, and they utilize less than half the recommended dosage of pancreatic enzymes. The brothers culture only methicillin-sensitive Staphylococcus aureus, and have never cultured any other bacteria. Highly effective modulator therapies, such as elexacaftor/tezacaftor/ivacaftor, do not substantially reduce infection and inflammation in vivo in CF patients, and thus these three case reports are of special note in terms of suggesting adjunct therapeutic approaches. Finally, these three cases also raise important questions about standard CF care guidelines.

• • Three adult brothers, delF508 cystic fibrosis (CF) homozygotes, maintain unusually preserved clinical condition absent standard CF care.
• • An alternative CF treatment regimen has kept their lung function, weight/height, and lab parameters normal, with low pancreatic enzyme dose.
• • The brothers culture only methicillin-sensitive Staphylococcus aureus, and have never cultured any other bacteria.
• • Highly effective modulator therapies (HEMT) for CF do not substantially reduce infection and inflammation in vivo; these cases are thus of note.
• • These cases also raise important questions about standard CF care guidelines.

1. Introduction

Cystic fibrosis (CF) is a serious and life-shortening genetic disorder affecting approximately 70,000 persons worldwide [ 1 ]. Respiratory failure is the foremost cause of death in CF patients, and lung transplantation is often considered in end-stage CF disease. For those born with CF in the last five years, median predicted survival age is now 44, which is decades longer than survival rates in the recent past [ 2 ]. Indeed, new advances in CF modulator therapy and CF gene therapy may eventually provide a normal life expectancy for these individuals.

A key approach in fighting the ravages of CF while waiting for more advanced treatments to be developed has been to slow the inexorable decline in lung function. Typical rate of lung function decline in CF is approximately −1.2 to −1.6 FEV1% per year [ 3 ]. Rate of decline is strongly associated with type of CF mutation. The three most severe classes of CFTR, Classes I, II, and III, represent defects in protein production, protein processing, and protein regulation, respectively [ 4 ]. The most common CF-causing mutation is delF508, occurring in 70% of cases, which is a Class II mutation [ 5 ]. Being homozygous for the delF508 mutation confers a severe phenotype, including pancreatic insufficiency and a steeper rate of decline in lung function over time [ 6 ]. In the United States, it is estimated that approximately 50% of those with cystic fibrosis are homozygous for delF508 [ 7 ]. Standard clinical care for severe mutation cases is often aggressive, including but not limited to daily airway clearance, use of pancreatic enzymes at the level of 500-2,500 lipase units/kg/meal (and enteric feeding if adequate weight percentile cannot be maintained), common and repeated use of oral, inhaled and intravenous antibiotics, daily intake of water-miscible versions of fat-soluble vitamins, and quarterly CF Clinic visits where lung function parameters and cultures of lung bacteria and fungi are assessed [ 8 , 9 ]. Pulmonary exacerbations often result in hospitalization, which may occur one or more times per year, typically lasting 14–21 days and including intensive antibiotic treatment and chest physical therapy. Everyday treatment burden is high, with estimates of 2–3 hours per day, with adherence at an estimated 50% or less [ 10 ]. The mean annual cost of standard supportive CF care in the US in 2016 (in 2019 dollars), before CFTR modulator therapies, was estimated to average $77,143, with severe non-transplant cases experiencing multiple pulmonary exacerbations costing on average triple or quadruple that amount [ 11 ]. With the average cost of elexacaftor/tezacaftor/ivacaftor (Trikafta) treatment currently over $311,000 per year, average standard supportive CF care costs were expected to double in 2019 [ 12 ] and increase further over time, perhaps quadrupling, with wider adoption of that treatment by all eligible patients.

Here we report on three adult brothers who are delF508 homozygotes, and yet who have maintained an unusually preserved clinical profile in the absence of standard CF clinical care. At the time of this writing, Brother A is 23 years old, Brother B is 21 years old, and Brother C is 18 years old. They are full-blooded siblings.

2. Case reports

2.1. brother a.

Brother A, now aged 23, was born full-term weighing 10 lbs. 2 oz. to a carrier mother experiencing gestational diabetes who subsequently breastfed him. His weight percentile decreased significantly over time, and at 6 months, after a course of oral antibiotics for a suspected ear infection, he developed a severe Vitamin K deficiency manifesting in quarter-sized black bruises on his body, as well as Pseudo-Bartter Syndrome. He was hospitalized until IV fluids stabilized his condition and normalized his electrolytes. Vitamin K shots were also administered. At 9 months of age, he was diagnosed with cystic fibrosis, and the genetic mutation analysis identified him as a delF508 homozygote. Between the time of his hospitalization and his diagnosis, he suffered from malnutrition with accompanying protein edema and his weight percentile, which had been over 97th percentile when born, was under the 5th percentile adjusted for age and sex. Once started on pancreatic enzymes (CREON 5) after diagnosis, his weight percentile increased to approximately the 30th percentile.

Approximately one year after diagnosis, the parents of Brother A elected to depart from standard CF care, including an election to stop attending the CF Clinic, while continuing to be under the care of their family pediatrician. The treatment plan for the brothers is described in detail in a later section. The only prescription medicine taken during his childhood and continuing to this day remains CREON 5/6, with Brother A utilizing 4 CREON 5/6 per meal, less than half the lowest recommended dose for his weight. In the teen years, Brother A experienced three episodes of heat exhaustion requiring IV fluid stabilization in an emergency room, has had one endoscopic sinus cleaning for sinus pain at age 20, and also underwent an appendectomy for appendicitis at age 23, but otherwise has had no major clinical issues, though exhibiting digital clubbing. Brother A played ice hockey throughout his childhood and teen years. His height, weight, lung function, and lab results at age 23 are provided in Table 1 .

Clinical parameters, Brother A.

2.2. Brother B

Brother B, now aged 21, was born full-term, weighing 8 lbs. 8 oz., the mother supplementing with oral glutathione (GSH) during the pregnancy and subsequently breastfeeding him. Brother B has never attended a CF Clinic, was diagnosed at 2 weeks of age, and was under the care of the family's pediatrician only. Brother B's only prescription medication during his childhood was CREON 5/6, just as with Brother A, utilizing 4 capsules per meal. Brother B has never needed to be hospitalized or have surgery or antibiotics. While Brother B does not exhibit digital clubbing; when recovering from respiratory viruses, he does manifest a cough that lingers longer than it lingers for his brothers, though the cough ultimately resolves. Brother B played ice hockey in childhood and teen years, as well as participated in gymnastics, cross-country running, track and field, and weight-lifting. His height, weight, lung function, and lab results at age 21 are provided in Table 2 .

Clinical parameters, Brother B.

2.3. Brother C

Brother C, now aged 18, was born full-term weighing 9 lbs. 2 oz., the mother supplementing with oral glutathione (GSH) during the pregnancy and subsequently breastfeeding him. Brother C has never attended a CF Clinic, was diagnosed at 2 weeks of age, and was under the care of the family's pediatrician only. Brother C's only prescription medication during his childhood was CREON 5/6, just as with Brothers A and B, utilizing 4 capsules per meal. Brother C has never needed to be hospitalized, or have surgery or antibiotics. Brother C does not exhibit digital clubbing. Brother C played ice hockey in childhood and teen years, as well as participated in gymnastics. His height, weight, lung function, and lab results at age 18 are provided in Table 3 .

Clinical parameters, Brother C.

3. Description of treatment

Given the severity of the genotype involved and the almost complete non-adherence to standard CF guidelines (with the exception of a significantly lower-than-average dose of prescription pancreatic enzymes and a standard dose of water-miscible fat soluble vitamins), the preserved clinical profile of these three brothers is noteworthy. However, the family developed a regimen that went well beyond pancreatic enzymes and water-miscible vitamins. The treatment regimen is provided in Table 4 .

Description of Daily Regimen.

4. Discussion

There are several possibilities for the preserved clinical status of these three brothers in the absence of standard CF care:

• a) They avoided the CF Clinic setting. Recent research [ 13 ] has shown that Pseudomonas infections are more prevalent and lung function lower among CF patients in standard care versus CF patients in a telemedicine setting. It is possible these three brothers benefitted from not attending a standard CF Clinic, especially since during their childhood years at the turn of the century, Clinic infection control was not emphasized. For example, during Brother A's first few CF Clinic visits as an infant, families were expected to wait together in a communal area with communal toys, and health care professionals at the Clinic wore neither masks nor gloves as they moved from exam room to exam room.
• b) With the exception of Brother A, Brothers B and C have used no antibiotics at all. Brother A has only used antibiotics three times in his life; the first use in infancy precipitated Pseudo-Bartter Syndrome, leading to his diagnosis with cystic fibrosis. The other two uses were incident to endoscopic sinus scraping and an appendectomy. Recent research has shown the importance of the gut microbiome in maintenance of health (including respiratory function), digestion and immune signaling, and this is true in the case of cystic fibrosis as well [ [14] , [15] , [16] ]. As David Pride, Associate Director of Microbiology at UC San Diego, notes in an address to the 2019 North American Cystic Fibrosis Conference [ 17 ], “It is important to preserve our microbiomes because they play important roles in preventing pathogens from establishing infections, in the development of our immune systems to recognize and kill pathogens, and in metabolic processes such as the digestion of foods. Indiscriminate uses of antibiotics can have profound and long-lasting effects upon our microbiomes by killing many of the bacteria that make up our microbiome; thus, limiting their use may aid in keeping us healthy.”
• Prevalent, sometimes chronic, antibiotic use among CF patients results in a significant gut dysbiosis [ 18 ]. In addition, it has been noted that aggressive antibiotic use in CF, usually incident to the first manifestation of Staphylococcus aureus (SA), may allow Pseudomonas aeruginosa a greater foothold [ 19 ], and that aggressive treatment of Pseudomonas may, in turn, promote drug resistance and may allow additional bacteria, such as Stenotrophomonas maltophilia, an opportunity to proliferate [ 20 ]. Perhaps a preserved gut microbiome due to non-use of antibiotics may have played a role in the brothers' preserved clinical condition; this may also help account for the brothers’ significantly lower level of need for pancreatic enzymes. Perhaps also the decision not to aggressively treat their light to moderate growth of methicillin-sensitive SA may have precluded additional bacteria, including drug-resistant bacteria, from emerging.
• c) Other standard daily CF treatments were not employed, either, which might help account for their preserved clinical condition. For example, the brothers do not use bronchodilators; and beta-2 agonist bronchodilators, such as albuterol, have recently been shown to significantly reduce delF508 CFTR activation [ 21 ]. This reduction is even evident when CFTR modulators are used, with the finding of a more than 60% reduction of modulator-corrected CFTR activation in vitro, “sufficient to abrogate VX809/VX770 modulation of F508-del CFTR” [ 21 ]. In addition, the brothers do not use DNase, which has been associated with increased levels of neutrophil elastase in past research [ 22 ]. Last, after Brother A transitioned to his new treatment regimen at approximately 23 months of age, chest percussive therapy (CPT) was discontinued, and neither Brother B nor C underwent CPT at all. A Cochrane meta-review found that while CPT constituted the lion's share of treatment time burden in CF, the evidence that outcomes of CPT differed from no CPT was “very low quality” [ 23 ].
• d) Glutathione (GSH) is heavily emphasized in the brothers' daily regimen. Levels of GSH are strongly decreased in the extracellular milieu of CF patients, as its efflux from epithelial cells is compromised by CFTR mutation [ 24 ]. In the non-CF research literature, GSH in its ratio of reduced to oxidized forms (GSH:GSSG) has been shown to be the foundation of redox signaling in the body; GSH is also the body's primary water-soluble antioxidant and a potent mucolytic, and conserves NO through formation of GSNO. Given its pivotal roles, it is not surprising to find that GSH deficiency is noted in several other severe respiratory illnesses besides CF, including ARDS, COPD, IIP, IPF, IRDS, and DFA, and GSH deficiency is a key catalyst for (and GSH dosing a key treatment of) cachexia [ 24 ]. The use of GSH in the treatment of CF may reduce systemic inflammation, lessen the viscosity of mucus, and catalyze the efficacy of the immune system, including through GSNO. Indeed, a clinical study by Visca et al. found significantly increased BMI [ 25 ], significantly increased lung function [ 26 ], and even improved bacteriological results [ 27 ] from the daily use of oral glutathione in children with CF at a dose of 30 mg/lb body weight/day, spread out over 3–4 doses, over a time period of 6 months. In addition, the parents of these brothers noted a sudden increase in both saliva and appetite in Brother A after glutathione (GSH) was introduced when he was two years of age. Brothers B and C, on GSH from two weeks of birth (and with the mother supplementing with oral glutathione throughout pregnancy with these two brothers), never displayed low saliva or low appetite. The preserved clinical status of these three brothers may perhaps be related to this glutathione-heavy regimen.
• e) Other aspects of the brothers' regimen may offset their disease condition. The use of probiotics [ 28 ], the heavy emphasis on antioxidants in addition to glutathione (such as C, CoQ10, Alpha-lipoic acid, D, E, etc. [ 29 ]), amino acids (such as cysteine [ 30 ], carnitine [ 31 ], choline [ 32 , 33 ], taurine [ 34 ], and glycine [ 35 ]), curcumin [ 36 ], and additional digestive support beyond enzymes (lecithin, bile acid). It is possible that some or all of these supplementation efforts also helped to preserve the clinical status of the three brothers. In addition, exclusive breastfeeding of CF infants has been linked to significantly higher FEV1 at age 5 (difference significant at p ≤ 0.001 between breastfed and formula fed CF infants), perhaps contributing to the preservation of lung function beyond that time frame [ 37 ].
• f) Modifier alleles may be present. While no in-depth analysis of the brothers' genetic profile has been performed beyond the identification of their CF mutations, there are known modifier alleles that serve to lessen (or exacerbate) the severity of CF (see, for example [ 38 ]). It is possible all three brothers inherited some propitious set of modifier alleles.

5. Conclusion

In conclusion, while it is encouraging and heartening that new CF therapies, such as elexacaftor/tezacaftor/ivacaftor (Trikafta) and other HEMT (highly effective modulator therapies), now exist, it is instructive to consider how this family was able to preserve the clinical condition of three brothers, all delF508 homozygotes, in the absence of those therapies, and even in the absence of standard CF care. While HEMT certainly increase CFTR activity, there is substantially less effect on infection and inflammation in vivo [ 39 ]. As recently noted by Singh et al., “[I]f infection and inflammation become uncoupled from CFTR activity in established disease [due to HEMT use], drugs targeting CFTR may need to be initiated very early in life, or used in combination with agents that suppress infection and inflammation ” [ 39 ; emphasis ours]. These case reports may speak to that proposition.

Furthermore, each possible explanation for that preservation is an occasion for reflection on the current standard of CF care. We may feel to ask questions such as, “From the point of view of the patient's health, is the entire concept of the CF Clinic inherently flawed? Is the frequent, sometimes chronic, use of antibiotics and certain other medications in CF care a real double-edged sword for CF patients, with disadvantages possibly outweighing advantages in many cases? Are there measures we can take now, relatively inexpensive measures such as the use of glutathione (GSH) and other antioxidants and amino acids, that will help preserve the clinical status of CF patients, and that might synergize with cutting-edge treatments such as CFTR modulators to improve and safeguard health to an even greater degree, and which should be initiated as early in life as possible, possibly while the fetus is still in utero ?” The experience of these three brothers, so removed from standard CF care and yet so well preserved in their clinical status, highlights the need to consider such questions more urgently than we perhaps have heretofore considered them.

Funding sources

This work was supported by the Utah Valley Institute of Cystic Fibrosis, for publication costs only.

Acknowledgements

The author wishes to acknowledge Valerie M. Hudson, who assisted with the writing of this article.

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C ystic fibrosis (CF) is an autosomal recessive condition affecting approximately 30,000 Americans and 70,000 people worldwide. According to the Cystic Fibrosis Foundation ( Cystic Fibrosis Foundation, 2019a ), approximately 1,000 new cases are diagnosed yearly in the United States, with a known incidence of 1 per 3,900 live births. The disease prevalence varies greatly by ethnicity, with the highest prevalence occurring in Western European descendants and within the Ashkenazi Jewish population.

The CF gene, located on chromosome 7, was first identified in 1989. The disease process is caused by a mutation to the gene that encodes for the CF transmembrane conductance regulator (CFTR) protein. This mutation alters the production, structure, and function of cyclic adenosine monophosphate (cAMP), a dependent transmembrane chloride channel carrier protein found in the exocrine mucus glands throughout the body. The mutated carrier protein is unable to transport chloride across the cell membrane, resulting in an electrolyte and charge imbalance. Diffusion of water across the cell membrane is thus impaired, resulting in the development of a viscous layer of mucus. The thick mucus obstructs the cell membranes, traps nearby bacteria, and incites a local inflammatory response. Subsequent bacterial colonization occurs at an early age and ultimately this repetitive infectious process leads to progressive inflammatory damage to the organs involved in individuals with CF.

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Primary Ewing sarcoma of the kidney: a rare entity with diagnostic challenges

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Rihane El Mohtarim, Taha Yassine Aaboudech, Samia Sassi, Naji Rguieg, Amine Cherraqi, Ibrahima Diallo Dokal, Siham El Haddad, Nazik Allali, Latifa Chat, Laila Hessissen, Mounir Kisra, Lamiaa Rouas, Najat Lamalmi, Primary Ewing sarcoma of the kidney: a rare entity with diagnostic challenges, Journal of Surgical Case Reports , Volume 2024, Issue 6, June 2024, rjae390, https://doi.org/10.1093/jscr/rjae390

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Ewing sarcoma is a very rare tumour with aggressive behaviour and a poor prognosis. It tends to metastasize rapidly. Renal Ewing sarcoma is extremely rare, and only 48 cases have been reported in the literature. Herein, we report the case of a 14-year-old female presenting with a painful left flank swelling. Ultrasound and magnetic resonance imaging showed a large tumour invading the left kidney, heterogeneously enhanced after injection, associated with lymph nodes and peritoneal carcinomatosis. A thoraco-abdomino-pelvic computed tomography scan revealed pulmonary nodules and osteolytic lesions. A biopsy was performed, and histology, immunohistochemistry, and molecular studies confirmed the diagnosis of retroperitoneal Ewing sarcoma. Multi-agent chemotherapy followed by radical nephrectomy was performed, confirming the renal origin, and histology showed a post-therapeutical response. After a 1-year follow-up, there was no evidence of recurrence. We report this case to highlight the rarity of this entity and its challenging clinico-pathological diagnosis when presenting as a renal tumour.

Ewing sarcoma (EWS) is defined as a small round cell sarcoma showing gene fusions involving one member of the FET family of genes (usually EWSR1) and a member of the ETS family of transcription factors [ 1 ]. It occurs mostly in bones, while extraskeletal sites account for ~20%–30% of the cases [ 2 ]. Renal extraskeletal EWS is extremely rare, with 48 cases reported in the English literature to date [ 3 ]. It represents <1% of all renal tumours [ 4 ]. Definite diagnosis requires a pathological examination.

Herein, we report a new case of renal EWS in a 14-year-old female to highlight the rarity of this entity and its challenging clinico-pathological diagnosis when presenting as a renal tumour.

A 14-year-old girl presented to the department of paediatric surgery with a 2-month history of abdominal pain and swelling of the flank and left hypochondrium, associated with generalized fatigue, anorexia, and weight loss. Physical examination of the patient revealed a left hypochondrial painful mass.

The patient underwent sonography followed by magnetic resonance imaging (MRI), which showed a large lobulated retroperitoneal left tumour measuring 20 × 16 × 14 cm, which was hypointense on T1-weighted and heterogenous on T2-weighted images with necrotic components and contrast-enhancing after Gadolinium administration. This mass invaded the left kidney, causing homolateral pelvicalyceal dilatation ( Fig. 1 ). Routine staging for metastasis showed: lymph nodes and peritoneal carcinomatosis nodules, pulmonary nodules revealed on a thoraco-abdomino-pelvic computed tomography (CT) scans, and secondary-looking osteolytic lesions ( Fig. 2 ) confirmed by scintigraphy.

Abdominal MRI in axial T1 (A), T2 (B), and a T1 fat-saturated post contrast (Gadolinium) sequence (C), coronal T2 (D and E) showing a large retroperitoneal tumour process lateralized to the left, hypointense on T1-weighted, hyperintense, and heterogenous on T2-weighted images with central areas of necrosis and contrast-enhancing after Gadolinium administration. Lymph nodes and peritoneal carcinomatosis nodules are associated. Displacement of the vascular axes (D) and of the spleen of the left kidney responsible for left pelvicalyceal dilation (E).

Axial thoraco-abdominal CT image on the bone window showing lytic bone lesions of the left iliac wing, sacrum, and vertebral bodies and on the pulmonary window showing pulmonary nodules.

An ultrasound-guided biopsy was performed, and histopathology revealed medium-sized cells arranged in sheets and nests separated by fine fibro-vascular septae. The tumour cells had rounded to oval nuclei, finely granular chromatin, and pale-to-clear scanty cytoplasm ( Fig. 3A ). Immunohistochemistry showed positivity for: CD99, NKX2-2, FLI1, and vimentin ( Fig. 3B–D ). WT1, chromogranin, synaptophysin, CD45, CD3, CD20, desmin, and myogenin were negative. Therefore, nephroblastoma, neuroblastoma, lymphoma, and rhabdomyosarcoma were respectively eliminated. ERG was also negative.

Histologic and immunohistochemical staining photomicrographs show sheets of small blue cells, scant cytoplasm with round or oval nuclei (A; H-E stain; original magnification, ×400), membranous expression of CD99 (B; CD99; original magnification, ×200), nuclear expression of NKX2-2 (C; original magnification, ×200), cytoplasmic expression of vimentine (D; original magnification, ×200), and nuclear expression of FLI1 (E; original magnification ×200), findings that are characteristic for EWS.

A molecular study by fluorescent in situ hybridization confirmed the presence of an EWS-FLI1 fusion.

Based on radiological, pathological, and molecular findings, the definite diagnosis was retroperitoneal extra-skeletal EWS, although a primitive renal origin couldn’t be excluded.

The patient was referred to oncology department for treatment. The proposed regimen was two cures of VAC (vincristine, doxorubicin, and cyclophosphamide) and two cycles of alternating vincristine-doxorubicin-cyclophosphamide and ifosfamide-etoposide.

Post-therapeutical assessment showed a 94% response on the MRI. Therefore, the patient underwent radical nephrectomy, as intraoperative findings confirmed the primitive renal origin of the tumour ( Fig. 4A ). The specimen was sent to our department for pathological examination.

Intraoperative image showing the kidney and the tumour lesion (A) and the gross specimen of a nephroureterectomy (B) with histologic staining showing post-therapeutic changes of the tumour, consisting of fibrosis, necrosis, and inflammation (C; H-E stain; original magnification, ×200).

On gross, it was a well-circumscribed superior polar tumour measuring 7.3 × 7.8 × 5 cm with a whitish-yellow cut surface and largely necrotic appearance with an infiltrated capsule ( Fig. 4B ).

Microscopic findings showed extensive post-therapeutical changes consisting of fibrosis and necrosis (estimated at 95%) ( Fig. 4C ).

Scattered viable tumour cells were identical to those found in the previous biopsy. The tumour infiltrated the renal capsule. Hilar lymph nodes were negative for metastasis.

Immunohistochemistry confirmed the diagnosis of EWS.

The patient benefited from adjuvant chemotherapy (two cycles of VDC and IE). After a 1-year follow-up of the patient and maintenance treatment, clinical and imaging evidence demonstrated that there was no disease recurrence.

Renal EWS is a very rare tumour with aggressive behaviour and a poor prognosis. It tends to metastasize rapidly. The median age is 27 years old, with a slight male predominance [ 5 ]. The symptoms are not specific, including flank pain (84%), palpable mass (60%), and haematuria (38%) [ 6 ]. Radiological features are not specific and might be seen in many tumours, especially those seen in young adults, such as Wilms tumour, neuroblastoma, renal cell carcinoma, and lymphoma [ 7 , 8 ].

The definitive diagnosis of renal EWS is based on pathological, immunohistochemical, and molecular testing.

On gross, EWS presents as greyish-white tumours with variable areas of haemorrhage and necrosis [ 9 ].

Microscopically, most cases are composed of uniform small round cells with round nuclei, finely stippled chromatin, inconspicuous nucleoli, scant clear or eosinophilic cytoplasm, and indistinct cytoplasmic membranes. Homer wright rosettes are common in renal ES, confirming their neuroectodermal differentiation [ 10 ].

Immunohistochemistry plays a pivotal role in the diagnosis of renal EWS, as new markers have improved the diagnostic accuracy, including NKX2.2.

NK2.2 is a protein that regulates the expression of genes involved in the neuroendocrine/glial differentiation pathway. NKX2.2 is a specific marker targeting the fusion protein EWS-FLI-1. It shows a high sensitivity of 93% and a specificity of 89% [ 11 ]. CD99 and FLI-1 are commonly used for EWS, though there is ongoing discussion about their precision [ 11 ].

The most frequent translocation in EWS is t (11,22) (q24;q12), which results in the EWSR1-FLI1 fusion transcript seen in almost 85% of cases. The second most common one is t (21,22) (q22;q12), which results in EWSR1-ERG in ~10% of cases [ 1 ]. Fluorescent in situ hybridization (FISH) is the gold standard method with high sensitivity (92.3%) and specificity (100%) [ 12 ].

In sum, morphological, immunophenotypic, and molecular findings are mandatory to allow for the diagnosis of renal EWS/PNET and to rule out other small round blue cell tumours as well as common renal neoplams.

The differential diagnosis is broad, including rhabdomyosarcoma, neuroblastoma, lymphoma, and nephroblastoma [ 13 ]. That was the differential diagnosis we have ruled out in our case using specific markers for each pathology.

The prognosis is poor, with an overall 5-year disease-free survival of 45%–55%. No recurrence was reported for our patient after a follow-up period of 1 year.

There is no established standard of treatment for renal EWS because of its scarcity. The management of EWS typically encompasses surgical resection, coupled with adjuvant chemotherapy, with or without neoadjuvant chemotherapy, and radiotherapy [ 3 ].

Vincristine, doxorubicin, ifosfamide, etoposide, actinomycin D, and cyclophosphamide are the most effective chemotherapy drugs [ 14 ].

The use of insulin-like growth factor 1 receptor antibodies in molecularly targeted treatment has shown some promising potential in EWS [ 15 ].

Renal EWS is a diagnostically challenging rare malignant tumour that should be kept in the differential diagnosis of small blue cell renal tumours. The radiological features are not specific, and diagnostic certainty is based on morphological, immunohistochemical, and molecular aspects. There is a need for a larger series to assess the prognosis and to define an effective therapy regimen.

All authors read and approved the final manuscript.

None declared.

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Abboud A , Masrouha K , Saliba M , et al.  Extraskeletal Ewing sarcoma: diagnosis, management and prognosis . Oncol Lett 2021 ; 21 : 354 . https://doi.org/10.3892/ol.2021.12615 .

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