Introduction

Non-Invasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features (NIFTP) was introduced in 2016 to address a subset of tumors previously classified as follicular variant papillary thyroid carcinoma (FVPTC). The reclassification was aimed at reducing overtreatment, as NIFTP carries an excellent prognosis and should not be considered a carcinoma. This blog will elaborate on how to differentiate NIFTP from other similar thyroid neoplasms, such as FVPTC, focusing on histopathological criteria, molecular differences, and diagnostic challenges.

Try to answer these questions before moving ahead

Find a zoomable slide of a 37 – year old patient diagnosed as NIFTP after several sections below. Interactive slide: Encapsulated lesion with nuclear features resembling papillary carcinoma but lacking invasion.

DIAGNOSTIC CRITERIA

The diagnosis of NIFTP relies on strict criteria that ensure its non-invasive and indolent nature. The following are the essential histopathologic features:

1. Encapsulation or Clear Demarcation: The lesion must be completely encapsulated or clearly demarcated.
2. Follicular Growth Pattern: The growth pattern should be predominantly follicular, without true papillae.
3. Nuclear Features of Papillary Carcinoma: Presence of nuclear changes typical of papillary thyroid carcinoma, such as nuclear enlargement, elongation, and membrane irregularities, but with a lower degree of severity. (Nuclear score 2-3)- find more details regarding nuclear score in the image below.
4. No Vascular or Capsular Invasion: Absence of invasion is crucial for the diagnosis.
5. Absence of Psammoma Bodies: True psammoma bodies should not be present.
6. No Tumor Necrosis or High Mitotic Activity: The lesion should lack high-risk features like necrosis and increased mitotic activity.

Criteria and Examples for Scoring Nuclear Features

Differentiating NIFTP from FVPTC and Other Follicular Lesions

Differentiation between NIFTP and FVPTC or other follicular lesions hinges on several key factors:

Feature	NIFTP	FVPTC	Follicular Adenoma
Encapsulation	Always encapsulated or well-demarcated	May be encapsulated or infiltrative	Encapsulated
Papillae Presence	Absent	Present in infiltrative areas	Absent
Nuclear Features	Present, less severe	Pronounced nuclear features (Grade III-IV)	Absent or minimal nuclear atypia
Capsular/Vascular Invasion	Absent	Often present	Absent
Molecular Alterations	RAS mutations (NRAS, HRAS)	BRAF mutations (common in classical PTC)	RAS mutations (NRAS, HRAS)

Molecular Differences

Molecular profiling plays a crucial role in differentiating NIFTP from other thyroid lesions:

• NIFTP: The most common genetic alterations include RAS mutations, particularly NRAS and HRAS. BRAF V600E mutation is consistently absent in NIFTP, a feature that distinguishes it from classic and infiltrative FVPTC.
• FVPTC: Characterized by a higher prevalence of BRAF mutations, particularly in the infiltrative subtypes. Additionally, FVPTC may harbor RAS mutations, though less frequently than NIFTP.
• Other Follicular Lesions: Follicular adenomas also exhibit RAS mutations but lack the nuclear features of papillary carcinoma.

Practical Diagnostic Flowchart

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Conclusion

The introduction of NIFTP has significantly impacted the management of thyroid neoplasms by distinguishing non-invasive lesions from aggressive carcinomas. By adhering to strict histopathologic criteria and utilizing molecular profiling, pathologists can make accurate diagnoses, thereby preventing unnecessary aggressive treatment. Awareness of the subtle differences between NIFTP and FVPTC is key to ensuring appropriate patient care.

References

• WHO Classification of Tumors: Endocrine Tumors. 5th Edition.
• Nikiforov YE, et al. Nomenclature Revision for Encapsulated Follicular Variant of Papillary Thyroid Carcinoma. JAMA Oncology, 2016.

Approach Based Course- Advanced Histopathology and Cytology