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World Health Organization Reporting System for Soft Tissue Cytopathology: A Concise Review with a Practical Diagnostic Approach

  • Marilyn M. Bui* 
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Abstract

Background and objectives

Soft tissue cytopathology plays a vital role in the diagnosis and management of soft tissue neoplasms, necessitating a standardized classification system to improve diagnostic accuracy and guide clinical decision-making. This article provides a concise review of the World Health Organization (WHO) Reporting System for Soft Tissue Cytopathology and presents a practical diagnostic approach to soft tissue cytopathology.

Methods

The WHO Reporting System is reviewed in conjunction with relevant literature. The reporting system employs a six-category framework: non-diagnostic, benign, atypical, soft tissue neoplasm of uncertain malignant potential, suspicious for malignancy, and malignant. Each category is associated with a corresponding risk of malignancy and recommended clinical management guidelines. This classification aligns with the WHO Classification of Soft Tissue and Bone Tumours (5th edition) and incorporates cytomorphologic features, ancillary studies, and clinical correlation to enhance diagnostic reproducibility and communication among pathologists and clinicians.

Results

The system supports a probabilistic approach to risk stratification, enabling more consistent diagnostic and therapeutic strategies.

Conclusions

As molecular diagnostics and immunocytochemistry continue to advance, this framework provides a robust foundation for the interpretation of soft tissue fine-needle aspiration biopsies and optimized patient care.

Keywords

Soft tissue tumor, Fine-needle aspiration biopsy, Report, Immunohistochemistry, Immunocytochemistry, Molecular testing, Risk for malignancy, Pathology, Cytopathology, Standardization, Diagnosis, Management

Introduction

Cytopathology is a critical component of the diagnostic pathway for soft tissue neoplasms. Fine-needle aspiration biopsy (FNAB) has been widely adopted in clinical practice as a minimally invasive method for evaluating both primary and metastatic lesions, owing to its high diagnostic yield, cost-effectiveness, and ability to rapidly guide patient management. However, despite its utility, soft tissue FNAB has historically lacked a universally accepted standardized reporting system and consistent terminology. This has resulted in challenges related to interobserver variability and diagnostic interpretation. Reported interobserver variability rates of 20–30% prior to standardization highlight the need for a more consistent reporting framework and strongly justify its implementation.1 Recognizing these issues, a group of experts—through the collaborative efforts of the International Academy of Cytology, the International Agency for Research on Cancer, and the World Health Organization (WHO)—recently developed the WHO Reporting System for Soft Tissue Cytopathology. This system aims to establish a structured diagnostic framework that enhances accuracy, reproducibility, and clinical relevance.1–4 It is aligned with the 5th edition of the WHO Classification of Soft Tissue and Bone Tumours, providing enhanced contextual accuracy.5

The diagnosis of soft tissue tumors via FNAB presents unique challenges due to the broad morphological spectrum of mesenchymal neoplasms, frequent cytological overlap between benign and malignant lesions, and the inherent subjectivity of cytopathologic interpretation. Unlike epithelial tumors, which often display well-defined cytological features, many soft tissue tumors exhibit subtle cytomorphologic variations that demand careful interpretation. Additionally, the WHO Classification of Soft Tissue and Bone Tumours (5th edition) includes limited content on cytology,5 further underscoring the need for a dedicated reporting system. In recent years, there has been a growing emphasis on risk stratification, similar to systems such as the Bethesda system for thyroid cytopathology, to guide clinical decision-making more effectively. The implementation of a standardized classification system offers a clear, reproducible method for categorizing FNAB results, thereby improving diagnostic precision and informing appropriate management strategies.

As a practicing bone and soft tissue pathologist, cytopathologist, and chapter contributor to this book, I had the privilege of reviewing the material prior to publication. This paper presents an overview of the WHO Reporting System for Soft Tissue Cytopathology, detailing each diagnostic category, its associated risk of malignancy (ROM), clinical relevance, and corresponding management strategies. By establishing a standardized lexicon and diagnostic approach, this system promotes accurate, reproducible, and clinically meaningful cytopathological interpretations, ultimately ensuring optimal patient care.

Standardization of reporting and practical diagnostic approach

To ensure clarity, consistency, and clinical applicability, the WHO Reporting System for Soft Tissue Cytopathology recommends that every soft tissue FNAB report follow a structured format with clearly defined diagnostic categories. Each report should begin with one of six primary diagnostic categories, followed by a detailed cytopathological description, risk assessment, and management recommendations. This structured approach enhances diagnostic accuracy, facilitates communication between cytopathologists and clinicians, and provides a probabilistic framework for risk stratification and patient care.

Primary diagnostic categories and associated ROM

A fundamental component of the reporting system is the primary diagnostic category, which assigns every FNAB interpretation to one of six standardized classifications: non-diagnostic, benign, atypical, soft tissue neoplasm of uncertain malignant potential (STNUMP), suspicious for malignancy, and malignant. These categories serve as a universal lexicon for reporting soft tissue FNAB results and ensure cytopathologists convey diagnostic findings in a standardized and reproducible manner (Table 1). The assigned category determines subsequent risk stratification, the need for further testing, and management recommendations.

Table 1

The WHO Reporting System for Soft Tissue Cytopathology – diagnostic categories, modified

CategoryDefinitionCommon findingsExamples
Non-diagnosticThe sample lacks adequate material in quantity or quality for a meaningful or reliable diagnosisScant material, necrotic debris, obscuring blood, crushed cells, acellular, or poor preservationAcellular aspirates, extensive necrosis, and blood-contaminated samples
BenignFNAB findings indicate unequivocal benign or a benign soft tissue neoplasmInflammation, uniform spindle or adipocytic cells, no significant atypia, no mitotic activity, background matrix consistent with benign tissueInflammation, lipoma, ganglion cyst, fibromatosis, moositis ossificans, tenosynovial giant cell tumor
AtypicalFNAB reveals cytological features that are not clear to determine tumor or not, or they are mostly benign, minimally worrisome for malignancy, but not sufficient for suspicious for malignancyVariable cellularity, variable nuclear features, mild atypia and possible low mitotic activityLipomatous tumor, low grade spindle cell proliferation, schwannoma with degenerative changes
Soft tissue neoplasm of uncertain malignant potential (STNUMP)FNAB demonstrates features of a mesenchymal neoplasm but lacks conclusive criteria to classify it as benign or malignantVariable cellularity, atypia, or mitotic figures, absence of necrosis or clear malignant features, possible myxoid or fibrotic backgroundSolitary fibrous tumor, myxoid soft tissue neoplasm, low-grade spindle cell tumor, smooth muscle tumor, dermatofibrosarcoma protuberans
Suspicious for malignancyFNAB findings are highly worrisome for malignancy but not definitiveVariable cellularity, increased nuclear pleomorphism and mitotic activity, occasional necrosis, may be short of quantitative or qualitative features for a definitive diagnosis of malignancyAtypical lipomatous tumor, low grade myxofibrosarcoma, gastrointestinal stromal tumor
MalignantFNAB findings are diagnostic of a malignant soft tissue neoplasmHigh cellularity, marked nuclear pleomorphism, high mitotic index, necrosis, abnormal architecture, and infiltrative growth patternLiposarcomas, leiomyosarcoma, synovial sarcoma, high-grade myxofibrosarcoma,
epithelioid sarcoma, Ewing sarcoma

In summary, every FNAB interpretation should be assigned to one of the following six primary diagnostic categories:

  • Non-diagnostic/Insufficient/Inadequate;

  • Benign;

  • Atypical;

  • STNUMP;

  • Suspicious for malignancy;

  • Malignant.

Each diagnostic category is associated with an estimated ROM, providing a probabilistic approach to malignancy risk. The ROM estimates are derived from multi-institutional validation studies to ensure transparency in risk assessment.2 ROM estimates should be presented as follows:

  • Non-diagnostic –29.9% (9-42%);

  • Benign – 2.5% (0-4%);

  • Atypical – 39.6% (46%);

  • STNUMP – 51.4% (20-27%);

  • Suspicious for malignancy – 68.2% (71-80%);

  • Malignant – 97.7% (91-100%).

ROM assessments should be based on institutional data and published literature to ensure evidence-based risk stratification.

Cytopathological description

The cytopathological description in the report could provide a concise yet detailed summary of microscopic findings, including cellularity (low, moderate, or high), cell arrangement (cohesive clusters, dispersed single cells, three-dimensional aggregates), nuclear features (pleomorphism, chromatin pattern, nucleoli), cytoplasmic characteristics (spindle, epithelioid, vacuolated, clear, or oncocytic cells), and background elements (necrosis, myxoid stroma, inflammatory infiltrates, mucin, or extracellular matrix). Special attention should be given to the presence of mitotic activity, atypical mitoses, or necrotic debris, as these features may indicate higher-grade lesions. These cytopathological findings assist in categorizing lesions into their respective risk groups and guide decisions regarding ancillary testing.

In summary, key components of the description of cytomorphological features include:

  • Cellularity (low, moderate, high);

  • Cell arrangement (cohesive clusters, dispersed single cells, three-dimensional aggregates);

  • Nuclear features (pleomorphism, chromatin pattern, nucleoli);

  • Cytoplasmic characteristics (spindle, epithelioid, vacuolated, clear, or oncocytic cells);

  • Background elements (necrosis, myxoid stroma, inflammatory infiltrates, mucin, or extracellular matrix);

  • Mitotic activity and atypical mitoses, if present.

Ancillary testing

When FNAB alone is insufficient for a definitive diagnosis and the tissue cell block is adequate, ancillary studies should be incorporated to refine tumor classification.6,7 Immunocytochemistry (ICC) can assist in distinguishing between different soft tissue neoplasms, particularly when differentiating mesenchymal, epithelial, and hematopoietic lesions.6 Key markers include S100 and SOX10 for schwannomas and melanomas; CD34 and STAT6 for solitary fibrous tumors; and desmin, smooth muscle actin, and MyoD1 for smooth muscle and skeletal muscle differentiation. Additionally, fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS) can provide molecular confirmation for certain tumors.8 For example, murine double minute 2 (MDM2) amplification confirms liposarcoma, Ewing sarcoma breakpoint region 1 (EWSR1) rearrangement is seen in Ewing sarcoma and myxoid liposarcoma, and KIT mutations are associated with gastrointestinal stromal tumors. When ancillary testing is performed, its findings should be incorporated into the report to aid in accurate classification and prognostication.

In summary, ancillary studies may be performed to refine tumor classification. These include:

ICC

  • Helps identify lineage-specific markers, differentiating mesenchymal, epithelial, and hematopoietic neoplasms;

  • Common markers include: S100, SOX10 (schwannoma, melanoma); CD34, STAT6 (solitary fibrous tumor); desmin, smooth muscle actin, MyoD1 (smooth and skeletal muscle differentiation).

FISH & NGS

  • Molecular testing identifies characteristic genetic alterations in soft tissue tumors;

  • Examples: MDM2 amplification (liposarcoma), EWSR1 rearrangement (Ewing sarcoma, myxoid liposarcoma), KIT mutations (gastrointestinal stromal tumor).

Clinical and imaging correlation

Soft tissue FNAB findings must be interpreted within the context of clinical and imaging findings to optimize diagnostic accuracy. Tumor location, size, and depth (deep-seated vs. superficial, intramuscular vs. subcutaneous), along with radiologic characteristics (well-circumscribed vs. infiltrative, presence of necrosis or calcifications), provide essential clues in differentiating benign from malignant lesions. Magnetic resonance imaging (MRI), computed tomography (CT), and ultrasound findings should be correlated with cytological results to refine the diagnostic approach. For indeterminate cases, multidisciplinary discussions with radiologists, oncologists, and surgeons can enhance diagnostic certainty and guide further management.

In summary, the report should include the context of clinical history and imaging studies. These include:

  • Tumor location, size, and depth (deep vs. superficial, intramuscular vs. subcutaneous);

  • Radiologic features (MRI, CT, ultrasound): well-circumscribed vs. infiltrative margins, necrotic, myxoid, or calcified components;

  • History of prior malignancies or metastatic disease.

Practical diagnostic approach

The practical step-by-step diagnostic approach for soft tissue cytology developed by the author is summarized in Figure 1 and detailed in Table 2.7 Similar approaches have been advocated by other pathologists.9

Practical diagnostic approach for soft tissue cytopathology.
Fig. 1  Practical diagnostic approach for soft tissue cytopathology.

This diagnostic algorithm was adapted from established protocols with modifications.7 FISH, fluorescence in situ hybridization; ICC, immunocytochemistry; STNUMP, soft tissue neoplasm of uncertain malignant potential.

Table 2

Summaries of differential diagnosis and ancillary testing based on morphology

Morphology categoryTumor typeKey featuresAncillary testing
Round cell tumorsEwing sarcomaSmall blue round cells, EWSR1::FLI1 or EWSR1::ERGFISH or NGS for rearrangement of EWSR1 or fusion of EWSR1::FLI1, or EWSR1::ERG; ICC CD99+, NKX2.2+, PKCBII+
RhabdomyosarcomaPrimitive round and spindle cells, rhabdomyoblasts, desmin+, myogenin+, MyoD1+ICC Desmin+, myogenin+, MyoD1+
LymphomaLymphoid cells, CD45 (LCA)+Flow cytometry for CD45 (LCA) and other CD markers
NeuroblastomaPrimitive small round cells with neuroblastic component, NSE+, Synaptophysin+, NMYC amplificationFISH or NGS for amplification of NMYC; ICC NSE+, synaptophysin+
Desmoplastic small round cell tumorNests of small round cells with desmoplasia, EWSR1::WT1, multilineage immunoreactivityFISH or NGS for rearrangement of EWSR1 or fusion of EWSR1::WT1; ICC WT1 (c-terminus)+, cytokeratin+, desmin (dot-like)+
Spindle cell tumorsLeiomyosarcomaPlump spindle cells with eosinophilic cytoplasm, cigar-shaped nuclei, fascicular pattern, showing nuclear pleomorphismICC Desmin+, SMA+, SMMS-1+, Caldesmon+
Synovial sarcomaSpindle cells, monophasic or biphasic pattern, SS18::SSX1/2/4FISH or NGS for rearrangement or fusion of SS18::SSX1/2/4; ICC TLE1+, SS18-SSX fusion protein+, SSX protein (C-terminus)+
Gastrointestinal stromal tumor (GIST)Spindle cells, epithelioid, or mixed morphology, perinuclear vacuoles, KIT (CD117)+(KIT) mutation for KIT and/or PDGFRA; ICC CD117+, DOG1+
FibrosarcomaHerringbone pattern, uniform spindle cellsICC Vimentin+, lacks specific markers
Nodular fasciitisReactive proliferation, feathery spindle cells, myxoid stromaFISH or NGS for USP6 rearrangement
Pleomorphic cell tumorsUndifferentiated pleomorphic sarcomaPleomorphic spindle and round cells, bizarre nucleiICC Vimentin+, no specific markers
Dedifferentiated liposarcomaPleomorphic, spindle, or epithelioid cells, lipoblasts, lipogenic differentiationFISH or NGS for MDM2 amplification; ICC MDM2+, CDK4+
Pleomorphic liposarcomaPleomorphic, lipoblastsNo MDM2 or CDK4 amplification; ICC Vimentin+, lacks specific markers
Pleomorphic rhabdomyosarcomaPleomorphic round cells, cross striations, desmin+ICC Desmin,+ myogenin+, MyoD1+
Malignant peripheral nerve sheath tumor (MPNST)Spindle cells with wavy nuclei, S100 variably positiveICC S100±, SOX10±, H3K27me3 loss
Epithelioid cell tumorsEpithelioid sarcomaEpithelioid cells with central necrosisICC, Cytokeratin+, EMA+, INI1 loss
Clear cell sarcomaEpithelioid, melanoma-like cells, EWSR1::ATF1FISH or NGS for fusion of EWSR1::ATF1;ICC S100+, SOX10+, HMB45+, Melan-A
Epithelioid angiosarcomaEpithelioid cells, vascular channels, ERG+ICC CD31+, ERG+
Alveolar soft part sarcomaNests of epithelioid cells, PAS+ crystalline inclusions, rich sinusoidal caplillariesFISH for fusion of ASPSCR1::TFE3; PAS+ crystals; ICC TFE3+
Myxoid tumorsMyxoid liposarcomaMyxoid background, signet ring-like lipoblasts, plexiform vasculatureFISH or NGS for DDIT3 rearrangement or fusion of FUS::DIT3 or EWSR1::DDIT3; ICC DDIT3+
MyxofibrosarcomaMyxoid stroma, curvilinear vessels, spindle cells with variable pleomorphismICC Vimentin+, lacks specific markers
Extraskeletal myxoid chondrosarcomaMyxoid stroma, cords of bland cells with eosinophilic cytoplasm, NR4A3 rearrangementFISH or NGS for rearmament of NR4A3 or fusion of EWSR1:: NR4A3
Myxoinflammatory fibroblastic sarcomaMyxoid stroma, inflammation, epithelioid or bizarre cellsICC Vimentin+, lacks specific markers

In summary, the practical diagnostic approach includes the following steps:

Step 1

Initial morphological assessment (pattern-based analysis):

Cellular pattern recognition:

  • Round cell tumors;

  • Spindle cell tumors;

  • Pleomorphic cell tumors;

  • Epithelioid cell tumors;

  • Myxoid tumors.

Cytological features:

  • Nuclear atypia;

  • Cellular cohesion;

  • Background matrix (myxoid, chondroid, necrotic, etc.);

  • Presence of lipoblasts, giant cells, or inflammation.

Step 2

Correlation with clinical and radiological features:

  • Age, site, growth pattern;

  • Imaging (MRI, CT, ultrasound);

  • Presence of metastases.

Step 3

Ancillary testing (confirmatory studies):

  • ICC (e.g., S100, MDM2, CDK4, desmin, myogenin);

  • Flow cytometry (lymphoid vs. non-lymphoid);

  • Molecular testing (FISH, NGS, polymerase chain reaction) (e.g., MDM2 amplification for liposarcomas, EWSR1 translocation for Ewing sarcoma);

  • Cytogenetics (chromosomal rearrangements in sarcomas).

Step 4

Final categorization:

  • Benign;

  • Atypical;

  • STNUMP;

  • Suspicious for malignancy;

  • Malignant.

Management recommendations

The final section of the report should include management recommendations tailored to the diagnostic category. After emphasizing that correlation with clinical and imaging findings is essential, the following are recommended:For non-diagnostic cases, repeat FNAB or core needle biopsy (CNB) is recommended, whereas benign lesions typically require only clinical follow-up. Atypical and STNUMP cases may require further workup with ancillary testing, biopsy, or excision. Suspicious for malignancy cases should be discussed in a multidisciplinary setting to determine the most appropriate next steps, including surgical biopsy or further molecular testing. Malignant diagnoses necessitate immediate referral for oncologic management, including additional staging, potential resection, and systemic therapy. The management plan should be tailored based on the diagnostic category, ROM, and clinical context to ensure the best possible patient outcome. Implied ROM and recommended clinical management are presented in Table 3.

Table 3

The WHO Reporting System for Soft Tissue Cytopathology – implied risk of malignancy (ROM) and recommended clinical management, modified

Diagnostic categoryRisk of malignancy (ROM)Recommended managements
Non-diagnostic29.9% (9-42%)Repeat FNAB with rapid on site evaluation (ROSE) or consider core needle biopsy (CNB) if persistently inadequate. Clinical and radiological correlation is necessary.
Benign2.5% (0-4%)Clinical follow-up based on imaging and clinical correlation.
Atypical39.6% (46%)Clinical and radiologic correlation is recommended. Repeat FNAB with ROSE or proceed with CNB. Ancillary testing may help refine the diagnosis.
Soft tissue neoplasm of uncertain malignant potential (STNUMP)51.4% (20-27%)Multidisciplinary discussion. Repeat FNAB or CNB. Excision may be warranted, particularly for deep-seated or enlarging lesions. Ancillary studies should be considered to further stratify risk
Suspicious for malignancy68.2% (71-80%)Ancillary molecular and immunocytochemical studies may help confirm malignancy and identify diagnostic, prognostic, and predictive biomarkers. Surgical biopsy or excision may be needed. Further imaging and clinical correlation with multidisciplinary discussion is recommended.
Malignant97.7% (91-100%)Immediate oncologic referral for staging and treatment. Management typically includes surgical resection, with consideration of radiation or systemic therapy based on tumor type and extent of disease. Biomarker information is important to guide patient management.

In summary, each FNAB report should provide recommendations for further evaluation and treatment, which may include:

  • Non-diagnostic: Repeat FNAB with rapid on site evaluation (ROSE) or consider core needle biopsy (CNB) if persistently inadequate; Clinical and radiological correlation is necessary;

  • Benign: Clinical follow-up for benign lesions with imaging surveillance;

  • Atypical: Clinical and radiologic correlation is recommended. Repeat FNAB with ROSE or proceed with CNB. Ancillary testing may help refine the diagnosis;

  • STNUMP: Multidisciplinary discussion. Repeat FNAB or CNB. Excision may be warranted, particularly for deep-seated or enlarging lesions. Ancillary studies should be considered to further stratify risk;

  • Malignant: Multidisciplinary team discussion for complex cases.

The management plan should be tailored based on the diagnostic category, ROM, and clinical scenario.

Conclusions

This structured reporting system aligns with the WHO Classification of Soft Tissue and Bone Tumours (5th edition), ensuring that cytopathological findings are reproducible, clinically actionable, and globally applicable. The approach integrates cytomorphological features, ancillary testing, and clinical correlation, emphasizing a probabilistic framework for risk stratification and decision-making. By providing clear diagnostic criteria, this system enables pathologists to contribute effectively to multidisciplinary patient management. Furthermore, advancements in molecular diagnostics, ICC, and NGS are expected to enhance the accuracy and specificity of FNAB-based diagnoses, reinforcing the role of cytopathology in the evaluation of soft tissue tumors.

A limitation of this publication is that it applies primarily to FNAB and can be extended to CNB; however, its relevance to touch imprint of soft tissue remains unclear. Given the increasing trend of obtaining CNBs of soft tissue lesions with rapid on-site evaluation for cellularity via touch imprint cytology, it would be valuable to determine whether this approach is also applicable in this context. Additionally, it is important to assess whether the clinical team supports this reporting system, as they are the primary end users with whom communication is intended. It will be interesting to examine the broader impact of this reporting system and explore its correlation with the upcoming 6th edition of the WHO Classification of Soft Tissue and Bone Tumours in the near future.

The hope is that by following this structured reporting format, the WHO Reporting System for Soft Tissue Cytopathology will ensure FNAB diagnoses are clear, reproducible, and clinically actionable. The integration of cytomorphological features, ROM assessment, ancillary testing, and clinical correlation will enhance the diagnostic accuracy of soft tissue FNAB and facilitate appropriate patient management. This standardized approach aligns with modern risk-based classification models and will improve communication among pathologists, radiologists, and oncologists, also ensure patient safety and high quality care.

It is important that the readers of this article refer to the exact wording and specific details related to the definition for each diagnostic category, risk of malignancy (ROM), and management recommendations as provided in the WHO Reporting System for Soft Tissue Cytopathology. The explanatory content in this review article has been adapted based on the author’s interpretation of the forthcoming book.

Declarations

Acknowledgement

Dr. Bui is grateful for the valuable assistance of Dr. Ghulam Rasool of Moffitt Cancer Center and Research Institute in preparing this manuscript.

Funding

The author has received no direct funding related to this work.

Conflict of interest

The author declares no conflict of interest related to this publication, except the author contributed as a co-author of some chapters of the WHO Reporting System for Soft Tissue Cytopathology.

Authors’ contributions

MMB is the sole author of the manuscript.

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Bui MM. World Health Organization Reporting System for Soft Tissue Cytopathology: A Concise Review with a Practical Diagnostic Approach. J Clin Transl Pathol. Published online: Jun 24, 2025. doi: 10.14218/JCTP.2025.00016.
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Article History
Received Revised Accepted Published
March 10, 2025 May 8, 2025 May 15, 2025 June 24, 2025
DOI http://dx.doi.org/10.14218/JCTP.2025.00016
  • Journal of Clinical and Translational Pathology
  • pISSN 2993-5202
  • eISSN 2771-165X
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World Health Organization Reporting System for Soft Tissue Cytopathology: A Concise Review with a Practical Diagnostic Approach

Marilyn M. Bui
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