First case description of a highly aggressive thoracopulmonary primitive neuroectodermal tumor in a Moroccan adult male

Abstract

Askin’s tumor is a rare, highly aggressive thoracopulmonary malignancy within the Ewing sarcoma family of tumors, predominantly affecting children and young adults, and is associated with a poor prognosis. We present a case of a 40-year-old male who is a current smoker with a 7-month history of a painful left anterior chest wall mass. Contrast-enhanced CT showed a large chest-wall tumor with rib lysis and pleural involvement. Histopathology confirmed a primitive neuroectodermal tumor, with immunohistochemistry positive for CD99, S-100, and synaptophysin. The patient was treated with VAC-IE poly-chemotherapy but experienced rapid radiological progression with extensive metastatic disease despite full-dose treatment. In the absence of an effective treatment for an aggressive disease, early intervention and multidisciplinary management are essential for timely control, prolonging survival while preserving quality of life.

Introduction

Primitive neuroectodermal tumors (PNETs) are rare, highly cellular, small round blue cell neoplasms characterized by aggressive local growth and an early propensity for systemic dissemination. Tumors arising in the thoracopulmonary soft tissues, historically described as Askin tumors, represent a distinct clinical pattern within this spectrum and may present in both children and adults^[1–3^]. Biologically and clinically, PNETs are closely related to Ewing sarcoma, and together they comprise the Ewing sarcoma family of tumors (ESFTs), a group defined by shared small-cell morphology, membranous CD99 expression, and characteristic chromosomal translocations that produce oncogenic fusion proteins^[4^].

Historically, PNETs have been subclassified by anatomical origin into central (cPNET) and peripheral (pPNET) forms, which arise in soft tissues outside the central nervous system and most commonly involve the chest wall, pelvis, abdomen, and extremities^[1^]. These tumors are inherently prone to misclassification because some immunophenotypic markers, including CD99, are highly sensitive but not specific, requiring that immunohistochemistry be interpreted in the broader clinicopathological and molecular context^[5^].

HIGHLIGHTS

• The incidence of Askin Tumor in Morocco is not well described.

• A few limited, unclearly detailed cases were highlighted.

• We report a recent update on a rare, aggressive Askin signature.

• A literature review was conducted.

Askin tumors are exceedingly uncommon and are often reported only as small series or case reports^[6,7^], while a population-level study of Ewing sarcoma highlights the overall rarity of these tumors and the consequent limitations in robust epidemiological data specifically for chest-wall PNETs ^[8^]. Clinically, the symptomatology consists of non-specific thoracic symptoms, including chest pain, cough, dyspnea, and a palpable mass, while radiological findings may include a heterogeneous soft-tissue mass, pleural effusion, and rib involvement – features that overlap with those of other small-round-cell neoplasms and thoracic malignancies^[6^]; therefore, optimal management relies on accurate diagnosis and classification, which require an integrated approach combining morphology, a targeted immunohistochemical panel, and molecular confirmation – most commonly, EWSR1 fusions^[6^].

Treatment involves chemotherapy-centered ESFT protocols, with surgery and radiotherapy as options for local control or with palliative intent, while outcomes are strongly influenced by stage at diagnosis, physician-adopted strategy, and tumor sensitivity. Beyond the canonical EWSR1 fusion, several recently reported markers, including NKX2-2, LINGO-1, STEAP1, EZH2, DKK2, MIR34A, and LGALS3BP, as well as genomic features such as loss of heterozygosity (LOH) and percentage genome altered (PGA), have emerged as promising diagnostic, prognostic, or therapeutic biomarkers in Ewing family – Askin tumors^[9–12^].

Here, we report the first Moroccan case of adult Askin’s tumor with a review of the contemporary literature to highlight and compare the clinicopathological features, diagnosis, and current therapeutic options.

Case presentation

A 40-year-old man with a 20-pack-year smoking history presented with a 7-month history of a progressively enlarging, painful left anterior chest wall mass. Over the preceding 5-months, he developed severe left-sided chest pain, productive cough, intermittent low-grade fevers, and an unusual 10-kg weight loss, without notable comorbidities, family history, regular medications, or drug allergies; his ECOG PS score was initially 1. The clinical examination identified a palpable lesion on the left anterior chest, characterized by firmness, immobility, and adherence to the overlying skin, measuring approximately 10 × 15 cm (Fig. 1). Analgesic treatment consisting of 50 mg of tramadol administered twice daily was prescribed.

Figure 1.

Left anterior chest wall mass measuring 10 × 15 cm.

Contrast-enhanced CT of the thorax, abdomen, and pelvis at presentation demonstrated a large anterolateral chest-wall mass centered on the anterior arc of the left fourth rib, measuring 130 × 118 × 101 mm, with a left internal mammary chain lymph node measuring 28 × 18 mm and five pulmonary nodules considered suspicious for metastatic disease. A restaging CT performed 2 months later, prior to treatment initiation, showed interval enlargement of the primary mass to 151 × 168 × 170 mm, with rib lysis and endothoracic extension without cardiac invasion. Additional findings included multiple ipsilateral pleural nodules, a metastatic lesion in the iliac bone, a pancreatic uncinate process lesion measuring 36.5 × 36 mm, and enlarged coeliomesenteric lymph nodes (Fig. 2a). All lesion measurements and response assessments were performed according to RECIST 1.1, with the large chest-wall mass (Askin tumor) designated as the primary target lesion for serial comparison. No PET-CT, bone scintigraphy, or brain MRI was performed because they were not considered clinically indicated by the treating team at the time of staging and restaging.

Figure 2.

Radiological evolution of the chest-wall mass centered on the anterior arc of the left fourth rib before initiation of treatment (a) and after four cycles of VAC-IE (b).

Baseline laboratory evaluation, including complete blood count, renal function, basic liver panel, electrolytes, coagulation profile, LDH, and albumin, was within institutional reference ranges with no clinically significant abnormalities. Tumor markers CA 19-9 and CEA were within normal limits at 2 U/mL and 0.7 ng/mL, respectively. Baseline cardiac assessment and renal function were normal for the planned chemotherapy regimen. Subsequently, the patient developed a persistent transaminase elevation (AST 98 U/L), which necessitated further clinical reassessment.

Histologically, the core-needle biopsy confirmed a highly cellular small round blue cell neoplasm with extensive necrosis, and light microscopy revealed sheets of monotonous small cells with scant cytoplasm and frequent mitoses (Fig. 3). Immunohistochemistry revealed strong membranous CD99 expression with positive S100 and synaptophysin, and negative pan-cytokeratin, vimentin, CD45, CD34, and CD56, with Ki-67 staining diffusely positive in approximately 80% of cells (Fig. 4), all of which support a diagnosis of peripheral primitive neuroectodermal tumor (pPNET). The diagnostic immunohistochemistry panel was completed within 10 days, and the interval from initial consultation to commencement of treatment was approximately 1 month.

Figure 3.

High-power field (×200) showing a malignant round-cell tumor proliferation with foci of tumor necrosis.

Figure 4.

(a) Diffuse staining for anti-S100 antibody; (b) diffuse nuclear staining for Ki-67 (high proliferation index); (c) diffuse membranous staining for CD99.

Due to the absence of essential EWSR1 antibodies and NGS testing for EWSR1 rearrangement confirmation in our pathology department, the test was deferred; this was compounded by the patient’s financial limitations, which further restricted testing in the private sector. A blinded slide review by an independent pathology laboratory was considered to confirm the diagnosis. We acknowledge the absence of molecular confirmation as an important limitation that may affect diagnostic precision and therapeutic decision-making.

Given the large tumor burden and presumed ESFT-spectrum disease, the patient was started on alternating VAC-IE poly-chemotherapy at full, non-intensified doses. Cycle A (VAC) consisted of vincristine 2 mg/m², doxorubicin 75 mg/m², and cyclophosphamide 1200 mg/m²; Cycle B (IE) consisted of ifosfamide 1800 mg/m²/day and etoposide 100 mg/m²/day on days 1-5. Cycles were scheduled every 3 weeks. No dose modification, reduction, or intensification was performed during the treatment course.

The first and second cycles were delivered on schedule. The patient experienced a later febrile episode that was treated with antibiotics and did not require postponement of therapy; granulocyte colony-stimulating factor (G-CSF) support was instituted thereafter. No antimicrobial prophylaxis was planned following episodes of neutropenia. The third cycle was delayed by 2 months because of recurrent grade 3 neutropenia despite G-CSF support. During this interval the patient developed severe non-hematologic toxicities graded according to CTCAE v4.0, including grade 3 diarrhea, grade 3 asthenia, grade 3 nausea and vomiting, grade 2 anorexia, and grade 1 anemia; ECOG PS declined to 2. Symptomatic supportive medications included ondansetron 8 mg twice daily, dexamethasone 10 mg three times daily, and loperamide 8–12 mg per day as indicated. The fourth cycle was postponed for an additional month because of these poorly tolerated adverse events. Cardiac monitoring was performed during therapy; left ventricular ejection fraction (LVEF) was rechecked and remained within institutional normal limits with no evidence of cardiotoxicity attributable to cumulative doxorubicin exposure.

After four cycles of VAC-IE (over approximately 7.5 months from presentation), restaging CT demonstrated radiological progression, in which the primary mass had enlarged to 210 × 226 × 206 mm, with increased pleural extension, new pleural and pericardial effusions, progression of the left ischiopubic bone metastasis, new subcutaneous satellite nodules, enlargement of the left ischiopubic ramus lesion with soft-tissue extension, and increased coelomesenteric lymphadenopathy (37 × 30 mm) (Fig. 2b). The previously noted pancreatic uncinate lesion remained radiologically stable.

At a multidisciplinary tumor board, the consensus was to proceed with second-line systemic therapy using gemcitabine-docetaxel, chosen because of limited alternative options and the patient’s prior intolerance to intensive ESFT regimens. The decision reflected the balance between disease extent, prior toxicities, and the goal of systemic disease control. Surgical resection was considered not feasible either initially or following progression because of the tumor’s large volume, extensive chest-wall destruction with rib lysis, endothoracic extension, and multifocal metastatic disease, rendering the lesion unresectable with unacceptable morbidity. Because the patient was not significantly symptomatic from the new pleural and pericardial effusions, no palliative thoracentesis, pericardial drainage, or cytologic sampling was performed at that time.

On the day scheduled to start second-line chemotherapy, the patient had persistent AST elevation to 98 U/L and grade 2 anemia, prompting further reassessment and temporary deferral of treatment. Over the subsequent 6 weeks, his respiratory status worsened due to progressive pulmonary metastatic disease and recurrent malignant pleural effusions. The patient ultimately died from respiratory failure before second-line chemotherapy could be administered.

Discussion

Adult presentation of thoracopulmonary pPNET (Askin tumor) is uncommon and frequently presents as large, rapidly progressive chest-wall masses, which complicate early recognition and staging, remaining, however, a clinical outlier internationally and a systems challenge regionally^[13^]. Accurate classification relies on an integrated approach – encompassing morphology, a focused immunohistochemical panel, and molecular confirmation of characteristic gene fusions (most commonly EWSR1-FLI1 or related partners)^[14^] – because each element refines prognosis and informs therapeutic selection; the absence of fusion testing, therefore, represents a meaningful diagnostic and management limitation in atypical adult cases^[15^]. Crucially, diagnostic confirmation in this context relies on an integrated approach; nevertheless, the inability to verify the EWSR1 rearrangement – unavailable in routine practice in Morocco – represents a recognized constraint for the definitive validation of the diagnosis of Ewing family tumors. In the absence of this molecular gold standard, an in-depth study of differential diagnoses was conducted; the immunohistochemical profile thus allowed the exclusion of lymphoblastic lymphoma (CD45-), rhabdomyosarcoma (vimentin-), or small cell carcinoma (pan-cytokeratin-). Although the positive co-expression of CD99, S100, and synaptophysin strongly points toward a peripheral PNET, it does not formally exclude Ewing-like sarcomas, particularly those associated with CIC or BCOR fusions^[16–18^]. These entities, generally defined by increased biological aggressiveness and partial resistance to standard protocols such as VACIE^[19,20^], could account for the rapid progression as well as the high Ki-67 proliferation index (80%) observed in our patient.

The therapeutic strategy for ESFT-spectrum tumors is inherently multimodal, contingent on the patient’s ECOG PS, organ function, and disease factors. The standard paradigm for curative intent requires both systemic control – commonly delivered as dose-intense regimens with VDC/IE or VAC/IE – and definitive local control by surgery and/or radiotherapy when an R0 resection or an effective radiotherapeutic plan can be achieved with minimal or acceptable morbidity^[4,21,22^]. Local therapy is favored when negative margins are realistic and functional outcomes are acceptable, while radiotherapy is an effective alternative for unresectable tumors or when surgery would be excessively morbid. Conversely, omission of surgery or radiotherapy is justified when the primary is anatomically unresectable and resection would incur prohibitive morbidity, or when synchronous metastatic disease predominates such that local control is unlikely to alter overall survival^[23^]. In fact, in our case, surgical intervention was deemed impracticable, as discussed during the MDT, given that the large tumor volume at diagnosis, measuring 130 mm, demonstrated extensive endothoracic extension with marked costal lysis and the synchronous presence of pulmonary and bone metastases, all of which made an R0 resection unrealistic and would likely precipitate clinical deterioration without clear therapeutic benefit. Accordingly, the treatment strategy prioritized palliative-intent systemic therapy with first-line VAC-IE; after progression following four cycles, the patient was scheduled for second-line systemic treatment, and reassessment for surgery or local radiotherapy to the primary was therefore not pursued.

In high-resource centers, centralized pathology review, rapid molecular testing, and protocolized toxicity mitigation support maintenance of dose intensity and timely local consolidation – factors associated with improved outcomes in localized disease. By contrast, delays in immunohistochemistry, lack of local fusion testing, and interruptions to chemotherapy commonly erode treatment intent and may accelerate progression in real-world, resource-constrained settings^[24^].

Population and institutional series consistently show that survival in ESFT is driven by systemic control plus complete local management, and that adult cohorts generally have worse outcomes than pediatric patients; disseminated or unresectable chest-wall disease rarely achieves durable control with standard regimens alone^[25,26^]. Regionally pragmatic priorities therefore include expediting pathology workflows, enabling access to EWSR1 testing via referral networks or pooled platforms, and standardizing supportive care (growth factor use, cardiotoxicity surveillance, nutritional and infection management) to preserve treatment intensity. Strengthening referral pathways to thoracic surgical and radiotherapy expertise and ensuring early, symptom-triggered palliative procedures (e.g., thoracentesis, pericardial drainage) within multidisciplinary tumor boards can reduce avoidable deterioration even when curative local therapy is not possible^[27^].

The clinical course observed in our patient aligns with published series indicating that adults with ESFT generally experience poorer outcomes than pediatric cohorts^[28,29^]. Adults less often tolerate intensive, dose-dense regimens and more frequently sustain treatment-limiting toxicities, which compromises delivered dose intensity and reduces the likelihood of durable remission^[30^], especially in disseminated or unresectable disease^[31,32^]. As highlighted by population and institutional series, survival is strictly dependent on both systemic control and complete local management^[33^]; however, achieving both objectives in adults is often difficult because tumors may behave more aggressively at presentation and because comorbidities, reduced physiologic reserve, and lower chemotherapy tolerance limit the feasibility of standard multimodal protocols^[34^].

Closing the outcome gap for adult Askin tumors requires coordinated system-level and research actions. Priority measures include shared molecular diagnostics and telepathology to enable timely, fusion-anchored diagnoses; active participation in international trial networks testing dose-dense and novel systemic regimens to generate evidence relevant to adults; and targeted investment in supportive and palliative infrastructure to stabilize patients so they can tolerate curative-intent therapy. Complementary strategies, from standardized pathways for proactive toxicity management to streamlined referral networks and rapid access to symptom-directed palliative care, will preserve treatment intensity, reduce avoidable interruptions, and improve quality of life^[35^].

This case highlights three interdependent priorities for Askin tumors in adults. First, timely molecular diagnostics and expert pathology review are essential to reduce diagnostic ambiguity and expand therapeutic options. Second, proactive toxicity management and multidisciplinary planning are necessary to preserve the dose intensity of ESFT regimens in real-world practice. Finally, equitable, supportive, and palliative infrastructure, including rapid pathology workflows and symptom-directed interventions, is required to stabilize patients and maintain treatment intent in resource-limited settings.

Conclusion

This case serves to underscore how system-level barriers compound the already aggressive biology of this disease. In this patient, advanced-stage presentation, recurrent treatment-limiting toxicities, and financial barriers to both therapy and molecular testing materially worsened clinical management and likely contributed to the poor outcome. Presenting this case, therefore, serves to highlight the real-world consequences of delayed diagnosis and constrained diagnostic and supportive resources.

Ethical approval

The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The Marrakech Faculty of Medicine and Pharmacy’s Ethical Review Committee gave its approval for the study. There was no need for a medical ethics assessment. Informed consent was also omitted in this case. The need for consent to participate in this study was waived by the Institutional Review Board of the Marrakech Faculty of Medicine and Pharmacy’s Ethical Review Committee in accordance with Moroccan Law No. 28-13 on the Protection of Persons Participating in Biomedical Research. This waiver is in compliance with national regulations that stipulate consent may be deemed unnecessary when the research poses minimal risk to participants and the rights and welfare of the participants are adequately protected.

Consent

Patient provided oral informed consent after receiving all the required information and having any questions answered.

Sources of funding

None.

Author contributions

Term: Y.A.T.; Conceptualization: Y.A.T.; Methodology: Y.A.T.; Validation: R.B.; Supervision: R.B.; Writing-original draft: Y.A.T.; Review, editing, and approval of the manuscript: All authors.

Conflicts of interest disclosure

The authors declare no conflicts of interest.

Research registration unique identifying number (UIN)

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Guarantor

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Provenance and peer review

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Data availability statement

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